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Bladder Tumors
EDITORS
MARK SOLOWAY,
ADRIENNE CARMACK, SAAD KHOURY
1st INTERNATIONAL CONSULTATION ON BLADDER TUMORS - HAWAII OCTOBER 3-7, 2004
CO-SPONSORED
BY
SIU (International Society of Urology),
ICUD (International Consultation on Urological Diseases),
EORTC Urology (European Organisation for Research and Treatment of Cancer)
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ISBN 0-9546956-4-X
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2
INTRODUCTION:
INTERNATIONAL CONSULTATION ON BLADDER TUMORS
understanding of the biology of bladder tumors
and will likely remain for many years.
The title of this text makes a statement. All bladder tumors are not malignant and thus, the title is
bladder tumors and not bladder cancer. This is
appropriate. Tumors of the urinary bladder are
heterogeneous. Not all neoplastic growths in the
bladder are a threat to the host. Papilloma, papillary urothelial neoplasms of low malignant potential and even most low-grade, non-invasive papillary tumors sometimes termed low grade transitional cell carcinoma do not behave as a malignancy
with the potential for invasion or metastasis. Yet,
almost 50% of our patients with bladder tumors
have one of these benign neoplasms and much of
our attention is directed at treating them.
I particularly want to express my deep appreciation to all of the chairs, vice-chairs and committee
members who unselfishly provided us with their
time and energy to accomplish this goal. This was
a labor of love. Each of the chairs had the task of
synthesizing the often diverse opinions of their
committee members and reaching a consensus
when possible.
I am particularly grateful to two individuals that
guided the project from its inception to completion. Saad Khoury formulated the concept of an
international consultation. I believe this is a worthy goal and although some may challenge individual guidelines, most would agree that a periodic
review of the literature with the discussion on
appropriate management is a productive endeavor.
Working with Mustafa Elhillali and the SIU, Saad
provided the challenge and the mechanism to
carry out the task. The second individual is
Adrienne Carmack. While only a mid-level urology trainee, Adrienne is an accomplished editor,
skilled communicator and most importantly, has
superb time management skills. She was able to
attend three international meetings, communicate
regularly with the committees, and helped me edit
the manuscripts while still taking part in a demanding residency program. Without email even
Adrienne could not have accomplished this task.
Bladder tumors are indeed a major health problem.
The prevalence of bladder tumors is high due in
part to their propensity to “recur” once resected
and the many etiologic factors related to their
development. Some of the causative agents are
known such as cigarette smoking and hair dyes
while others have yet to be determined. It is likely that many of the chemicals in our environment
are concentrated in the urine and capable of causing mutations in the bladder urothelium thus leading to a bladder neoplasm. It has been stated that
the cost of taking care of patients with bladder
tumors is among the highest of all neoplasms.
This text details the final report of the consultation
on bladder tumors and provides an extensive
resource for all those interested in this disease. It
has been an honor and privilege to chair this International Consultation on Bladder Tumors. I was
confident that the many experts throughout the
world would agree to share their expertise and participate in this major effort. I subdivided the subject of bladder tumors into eleven areas. Each
committee had the task of collecting information
on their subject area and, after an extensive
review, arrive at a consensus or guidelines.
Although there are relatively few randomized
trials dealing with bladder tumors, we have produced many guidelines whose foundation largely
rests on the experience of those who have studied
this disease for many years. Guidelines may change as new techniques, knowledge and treatments
evolve. Most of these, however, are based on an
Many of you will not have the opportunity to read
the entire text but will use this volume as a resource and select topics of interest. I will take the
chairman’s prerogative of highlighting some of the
guidelines and recommendations from the 11 committees.
Epidemiology and Diagnosis
Bladder tumors are common. It is the most common malignancy in some countries (Egypt) and
ranks very high in many others e.g. Turkey, China,
United States. Since we know some of the risk
factors, e.g. age, cigarette smoking, hair dyes,
there is an opportunity for early detection. Unfortunately many of our patients are diagnosed at a
stage when even our optimal treatments are only
3
palliative. Since we have effective treatments for
Ta – T1 urothelial tumors, it only seems reasonable to devote some resources to identifying
bladder cancer at an early stage. This strategy has
made an impact on some other tumors, e.g. breast,
prostate, cervix. Importantly, the majority of bladder tumors left untreated will eventually require
therapy so the problem of overdetection does not
seem pertinent.
proceeding with a radical cystectomy in a subset
of these patients, e.g. multifocal high grade T1
with CIS. The concept of a reTUR is a strong
recommendation in this group of patients given
the critical role of staging in the decision making
process. In general, this should be performed
within a few weeks of the initial endoscopic resection of a high grade Ta or T1 bladder cancer. One
must exclude muscle invasion since this would
change the treatment algorithm. Muscle must be
present in the resection specimen.
The committee urges pathologists and urologists
to adopt the 2004 WHO/ISUP classification which
divides grades into low or high eliminating the
ambiguous Grade 2 category.
BCG is the treatment of choice following resection of a high-grade Ta, CIS or T1 urothelial carcinoma. It is yet to be established that maintenance
BCG is necessary, although the majority of the
committee members felt that a minimum of oneyear maintenance has been shown to reduce the
recurrence rate if not the progression rate. The
three and six month evaluation is critical. If a high
grade tumor recurs or persists within this time
frame, one should consider proceeding without
undue delay to radical cystectomy.
Markers
The development of urine based tumor markers
provides an opportunity for early detection as well
as non-invasive surveillance following the initial
diagnosis of a bladder tumor. Of course, urologists will not abandon the cystoscope which is the
foundation of the diagnosis and initial treatment.
It is, however, invasive. Some of the monitoring
can be supplemented or substituted by a tumor
marker. This is applicable particularly for those
with low risk tumors. This chapter provides an
extensive review of cytology and the various markers.
The committee felt that following the initial resection of a high grade Ta or T1 tumor, a single dose
of post-operative intravesical chemotherapy is
appropriate to decrease the chance of tumor
implantation. This does not alter the recommendation to use BCG.
Low grade, non-invasive tumors
There is sufficient evidence from prospective randomized trials to recommend the instillation of
intravesical chemotherapy within hours of resection of low grade, Ta tumors provided that the
bladder wall remains intact. Upper tract monitoring is not necessary in these patients as the risk of
an upper tract urothelial tumor is very low. Office
fulguration is felt to be an acceptable mode of therapy for small, low grade “recurrences”.
Muscle invasive urothelial cancer
Radical cystectomy remains the optimal treatment
for tumors which invade the muscularis propria of
the bladder. There are occasional patients who
meet the criteria for bladder preservation, which
includes a “complete transurethral resection” followed by combination chemotherapy and radiation therapy. Careful and persistent monitoring is
necessary. This approach requires the expertise of
three disciplines (urology, radiation and medical
oncology). The presence of hydronephrosis is
generally felt to exclude the role of bladder preservation.
High grade Ta, carcinoma in situ, and T1 (2
committees)
The term bladder cancer is appropriate for these
grades and stages. Not only is the likelihood of a
subsequent tumor following initial resection high
but there is a risk of progression to a higher stage.
The clinician must assure removal of all of the
tumor, accurate staging, and make an effort to
minimize the likelihood of a subsequent tumor.
Depending on certain prognostic factors such as
multifocality and stage, one might even consider
The committee commented on two of the problems related to this group of patients. A delay
from diagnosis to cystectomy greater than 12
weeks is an adverse prognostic factor. Many
patients who would ordinarily be candidates for
cystectomy, are not having an opportunity to have
this therapy. This needs to be explored further.
4
Urinary diversion
Urothelial carcinoma of the prostate
Twenty years ago virtually all patients had an
external appliance upon removal of the urinary
bladder. With the introduction of a continent cutaneous diversion and subsequently the development of an orthotopic neobladder. Fifty percent
of patients now avoid an external appliance.
Ileum is the bowel segment of choice for construction of an orthotopic neobladder. Patients must be
motivated and understand the possibility of nocturnal incontinence and the need for clean intermittent catheterization. The orthotopic neobladder
as currently performed in many major medical
centers has the same morbidity as other forms of
urinary diversion and patient acceptance has been
excellent.
It is important for the urologist to monitor the
prostatic urethra, particularly in the presence of a
high grade urothelial carcinoma of the bladder.
Treatment for urothelial carcinoma of the prostate
depends on the stage: confined to the urothelium,
involvement of the prostatic ducts or stromal invasion. The treatment for carcinoma confined to the
urothelium is transurethral resection followed by
BCG if the cancer is high grade. Once the tumor
involves the stroma radical cystectomy is necessary, assuming that the patient is a candidate for
major surgery. When the tumor involves only the
prostatic ducts, some would proceed with transurethral resection plus BCG while others think this
warrants proceeding to cystectomy.
Radiation therapy
Non-urothelial carcinoma of the bladder
External beam radiation therapy remains a common form of treatment for muscle-invasive bladder cancer in many geographic areas and in particular in patients older than 75. There are groups
of patients in which the success rate is low and this
includes patients with ureteral obstruction and clinical stages T3-T4. Concurrent cisplatin should
be administered along with external beam radiation therapy unless there is a contraindication such
as impaired renal function. For the advanced clinical stages, multiagent systemic chemotherapy
should precede external beam radiation therapy.
Squamous cell carcinoma, adenocarcinoma and
small cell carcinoma are uncommon but important
neoplasms of the urinary bladder. Radical cystectomy is the treatment of choice for squamous cell
and adenocarcinoma. Systemic chemotherapy is a
critical component of the treatment for small cell
carcinoma of the bladder.
This has been only a few highlights from the
extensive amount of material that follows in this
book. Whenever possible, the authors have
attempted to provide guidelines and indicate the
grades of recommendation as identified in the
Oxford Center for Evidence-Based Medicine. On
behalf of all of those who worked so diligently in
this project, we sincerely hope that the information
provided will be used to help all of us optimize the
care of our patients with bladder tumors.
Systemic chemotherapy
Cisplatin-based multiagent systemic chemotherapy for urothelial cancer rarely provides a cure in
those who have metastasis; however, many
patients have significant palliation. The current
most active combinations consist of either MVAC
or gemcitabine plus cisplatin. Other combinations
have been explored and many are active.
Adverse risk factors for patients with clinically
localized muscle invasive bladder cancer include
lymphovascular invasion, hydronephrosis, stage
T3-T4 and prostatic stromal invasion. Such
patients can be considered for neoadjuvant chemotherapy although prospective randomized trials
show only a modest benefit with this approach.
There is insufficient evidence to recommend routine adjuvant chemotherapy for patients with pT2
and pT3 bladder cancer.
Mark S. Soloway, M.D.
Professor and Chairman
Department of Urology
University of Miami – Miller School of Medicine
Miami, Florida
5
MEMBERS OF THE COMMITTEES (by Committee)
Committee 1 Bladder Cancer:
Epidemiology, Staging and
Grading, and Diagnosis
(TURKEY),
Z.
KIRKALI
(USA),
T.
CHAN
(USA),
M.
MANOHARAN
F.
ALGABA
(SPAIN),
(SWEDEN),
C.
BUSCH
L.
CHENG
(USA),
(NETHERLANDS),
L.
KIEMENEY
(GERMANY),
M.
KRIEGMAIR
R.
MONTIRONI
(ITALY),
(USA),
W.
MURPHY
I.
SESTERHENN
(USA),
M.
TACHIBANA
(JAPAN),
(USA)
J.
WEIDER
Committee 4 High Grade Ta Urothelial
Carcinoma and Carcinoma
in Situ of the Bladder
(BELGIUM),
R.
SYLVESTER
(NETHERLANDS),
A.V.D MEIJDEN
(NETHERLANDS),
J.A. WITJES
(GERMANY),
G.
JAKSE
(JAPAN),
N.
NONOMURA
C.
CHENG
(SINGAPORE),
(MEXICO),
A.
TORRES
(AUSTRALIA),
R.
WATSON
K.H. KURTH
(NETHERLANDS)
Committee 5 T1 Urothelial Carcinoma
of the Bladder
(CANADA),
M.A.S JEWETT
A.M. NIEDER
(USA),
(ITALY),
M.
BRAUSI
(USA),
D.
LAMM
M.
O’DONNELL
(USA),
(JAPAN),
K.
TOMITA
(AUSTRALIA)
H.
WOO
Committee 2 Cytology And Tumor
Markers:Tumor Markers
Beyond Cytology
(USA),
V.B
LOKESHWAR
(JAPAN),
T.
HABUCHI
H.B. GROSSMAN
(USA),
(USA),
W.M. MURPHY
(USA),
G.P. HEMSTREET, III
S.H. HAUTMANN
(GERMANY),
(ITALY),
A.V. BONO
(USA),
R.H. GETZENBERG
P.
GOEBELL
(GERMANY),
B.J. SCHMITZ-DRÄGER (GERMANY),
M.
MARBERGER
(AUSTRIA),
(NETHERLANDS),
J. A. SCHALKEN
E.
MESSING
(USA),
Y.
FRADET
(CANADA),
(USA)
M.J. DROLLER
Committee 6 Muscle-Invasive Urothelial
Carcinoma of the Bladder
(USA),
S. B. MALKOWICZ
VAN POPPEL
(BELGIUM),
H.
(GERMANY),
G.
MICKISCH
V.
PANSADORO
(ITALY),
J.
THÜROFF
(GERMANY),
M.
SOLOWAY
(USA),
(USA),
S.
CHANG
M.
BENSON
(USA),
(JAPAN)
I.
FUKUI
Committee 7 Urinary
R. E. HAUTMANN
H.
ABOL-ENEIN
K.
HAFEZ
I.
HARA
W.
MANSSON
R. D. MILLS
J. D. MONTIE
A. I. SAGALOWSKY
J. P. STEIN
A.
STENZL
U.E. STUDER
B.G. VOLKMER
Committee 3 Low Grade, Ta
(Noninvasive) Urothelial
Carcinoma of the Bladder
(BELGIUM),
W.
OOSTERLINCK
E.
SOLSONA
(SPAIN),
H.
AKAZA
(JAPAN),
(SWEDEN),
C.
BUSCH
P.J. GOEBELL
(GERMANY),
P.-U. MALMSTRÖM
(SWEDEN),
(TURKEY),
H.
ÖZEN
P.
SVED
(USA)
6
Diversion
(GERMANY),
(EGYPT),
(USA),
(JAPAN),
(SWEDEN),
(UK),
(USA),
(USA),
(USA),
(GERMANY),
(SWITZERLAND),
(GERMANY)
Committee 8 Urothelial Carcinoma
of the Prostate
(SPAIN),
J.
PALOU
J.
BANIEL
(ISRAEL),
(CANADA),
L.
KLOTZ
D.
WOOD
(USA),
M.
COOKSON
(USA),
(USA),
S.
LERNER
S.
HORIE
(JAPAN),
M.
SCHOENBERG
(USA),
(SPAIN),
J.
ANGULO
(ITALY)
P.
BASSI
Committee 10 Radiotherapy for
Bladder Cancer
(CANADA),
M.
MILOSEVIC
M.
GOSPODAROWICZ (CANADA),
(USA),
A.
ZIETMAN
F.
ABBAS
(PAKISTAN),
K.
HAUSTERMANS
(BELGIUM),
(NETHERLANDS),
L.
MOONEN
(GERMANY),
C.
RÖDEL
M.
SCHOENBERG
(USA),
(USA)
W.
SHIPLEY
Committee 9 Chemotherapy for Bladder
Cancer: Treatment
Guidelines for Neoadjuvant
Chemotherapy, Bladder
Preservation, Adjuvant
Chemotherapy, and
Metastatic Cancer
(ITALY),
C.
STERNBERG
(USA),
S.M. DONAT
(SPAIN),
J.
BELLMUNT
R.E. MILLIKAN
(USA),
(USA),
W.
STADLER
(NETHERLANDS),
P.
DE MULDER
A.
SHERIF
(SWEDEN),
VON DER MAASE
(DENMARK),
H.
(JAPAN),
T.
TSUKAMOTO
M.
SOLOWAY
(USA)
Committee 11 Non-urothelial Cancer
of the Bladder
(EGYPT),
H.
ABOL-ENEIN
(USA),
B.R. KAVA
A.J.K. CARMACK
(USA)
7
CONTENTS
Summary of International Consultation on Urologic Disease Modified Oxford Center for
Evidence-based Medicine Grading System for Guideline Recommendations
10
Committee 1 Bladder Cancer: Epidemiology, Staging and Grading,
and Diagnosis
13
Z. KIRKALI (TURKEY), T. CHAN (USA), M. MANOHARAN (USA), F. ALGABA (SPAIN),
C. BUSCH (SWEDEN), L. CHENG (USA), L. KIEMENEY (NETHERLANDS),
M. KRIEGMAIR (GERMANY), R. MONTIRONI (ITALY, W. MURPHY (USA),
I. SESTERHENN (USA) M. TACHIBANA (JAPAN), J. WEIDER (USA)
Committee 2 Cytology And Tumor Markers:Tumor Markers Beyond Cytology
65
V. B. LOKESHWAR (USA), T. HABUCHI (JAPAN), H. B. GROSSMAN (USA),
W. M. MURPHY (USA), G. P. HEMSTREET, III (USA), S. H. HAUTMANN (GERMANY),
A. V. BONO (ITALY), R. H. GETZENBERG (USA), P. GOEBELL (GERMANY),
B. J. SCHMITZ-DRÄGER (GERMANY), M. MARBERGER (AUSTRIA),
J. A. SCHALKEN (NETHERLANDS), E. MESSING (USA), Y. FRADET (CANADA),
M. J. DROLLER (USA)
Committee 3 Low Grade, Ta (Noninvasive) Urothelial Carcinoma of the Bladder
139
W. OOSTERLINCK (BELGIUM), E. SOLSONA (SPAIN), H. AKAZA (JAPAN),
C. BUSCH (SWEDEN), P. J. GOEBELL (GERMANY), P.-U. MALMSTRÖM (SWEDEN),
H. ÖZEN (TURKEY), P. SVED (USA)
Committee 4 High Grade Ta Urothelial Carcinoma and Carcinoma in Situ of
the Bladder
165
R. SYLVESTER (BELGIUM), A. V.D. MEIJDEN (NETHERLANDS), J.A. WITJES (NETHERLANDS),
G. JAKSE (GERMANY), N. NONOMURA (JAPAN), C. CHENG (SINGAPORE),
A. TORRES (MEXICO), R. WATSON (AUSTRALIA), K.H. KURTH (NETHERLANDS)
Committee 5 T1 Urothelial Carcinoma of the Bladder
189
M.A.S. JEWETT (CANADA), A.M. NIEDER (USA), M. BRAUSI (ITALY), D. LAMM (USA),
M. O’DONNELL (USA), K. TOMITA (JAPAN), H. WOO (AUSTRALIA)
Committee 6 Muscle-Invasive Urothelial Carcinoma of the Bladder
S. B. MALKOWICZ (USA), H. VAN POPPEL (BELGIUM), G. MICKISCH (GERMANY),
V. PANSADORO (ITALY), J. THÜROFF (GERMANY), M. SOLOWAY (USA),
S. CHANG (USA), M. BENSON (USA), I. FUKUI (JAPAN)
8
219
Committee 7 Urinary Diversion
239
R. E. HAUTMANN (GERMANY), H. ABOL-ENEIN (EGYPT), K. HAFEZ (USA),
I. HARA (JAPAN), W. MANSSON (SWEDEN), R. D. MILLS (UK), J. D. MONTIE USA),
A. I. SAGALOWSKY (USA), J. P. STEIN (USA), A. STENZL (GERMANY),
U. E. STUDER (SWITZERLAND), B. G. VOLKMER (GERMANY)
Committee 8 Urothelial Carcinoma of the Prostate
309
J. PALOU (SPAIN), J. BANIEL (ISRAEL), L. KLOTZ (CANADA), D. WOOD (USA),
M. COOKSON (USA), S. LERNER (USA), S. HORIE (JAPAN), M. SCHOENBERG (USA),
J. ANGULO (SPAIN), P. BASSI (ITALY)
Committee 9 Chemotherapy for Bladder Cancer: Treatment Guidelines
for Neoadjuvant Chemotherapy, Bladder Preservation,
Adjuvant Chemotherapy, and Metastatic Cancer
335
C. STERNBERG (ITALY), S. M. DONAT (USA), J. BELLMUNT (SPAIN),
R. E. MILLIKAN (USA), W. STADLER (USA), P. DE MULDER (NETHERLANDS),
A. SHERIF (SWEDEN), H. VON DER MAASE (DENMARK), T. TSUKAMOTO (JAPAN),
M. SOLOWAY (USA)
Committee 10 Radiotherapy for Bladder Cancer
359
M. MILOSEVIC (CANADA), M. GOSPODAROWICZ (CANADA), A. ZIETMAN (USA),
F. ABBAS (PAKISTAN), K. HAUSTERMANS (BELGIUM), L. MOONEN (NETHERLANDS),
C. RÖDEL (GERMANY), M. SCHOENBERG (USA), W. SHIPLEY (USA)
Committee 11 Non-urothelial Cancer of the Bladder
H. ABOL-ENEIN (EGYPT), B.R. KAVA (USA),A.J.K. CARMACK (USA)
9
383
Summary of the International Consultation on Urologic Disease Modified Oxford System
for Levels of Evidence and Grades of Recommendations
Levels of Evidence
Level 1 Metanalysis of RCTs or a good quality RCT
Level 2 Low quality RCT or metanalysis of good quality prospective cohort studies
Level 3 Good quality retrospective case control studies or case series
Level 4 Expert opinion based on “first principles” or bench research, not on evidence
Grades of Recommendation
Grade A Usually consistent level 1 evidence
Grade B Consistent level 2 or 3 evidence or “majority evidence” from RCTs
Grade C Level 4 evidence, “majority evidence” from level 2/3 studies, expert opinion
Grade D No recommendation possible because of inadequate or conflicting evidence
*Adapted from Evidence-based medicine: Overview of the main steps for developing and grading
guideline recommendations, by P Abrams, A Grant, and S Khoury, January 2004
10
Bladder Tumors
EDITORS
MARK SOLOWAY,
ADRIENNE CARMACK, SAAD KHOURY
11
12
Committee 1
Bladder Cancer: Epidemiology, Staging
and Grading, and Diagnosis
Chair
Z. KIRKALI (TURKEY)
Vice Chairs
T. CHAN (USA)
M. MANOHARAN (USA)
Members
F. ALGABA (SPAIN)
C. BUSCH (SWEDEN)
L. CHENG (USA)
L. KIEMENEY (NETHERLANDS)
M. KRIEGMAIR (GERMANY)
R. MONTIRONI (ITALY)
W. MURPHY (USA)
I. SESTERHENN (USA)
M. TACHIBANA (JAPAN)
J. WEIDER (USA)
13
CONTENTS
I. EPIDEMIOLOGY OF BLADDER
CANCER
III. DIAGNOSIS
1. BLADDER CANCER SCREENING
1. INCIDENCE AND MORTALITY
2. SIGNS AND SYMPTOMS
2. ENVIRONMENTAL RISK FACTORS
3. URINARY CYTOPATHOLOGY
3. GENETIC SUSCEPTIBILITY
4. IMAGING OF BLADDER CANCER AT INITIAL
DIAGNOSIS
4. LIFESTYLE AND PROGNOSIS
5. CYSTOSCOPY
II. STAGING AND GRADING OF
BLADDER CANCER
6. TRANSURETHRAL RESECTION
TUMORS (TURBT)
1. CLASSIFICATION OF UROTHELIAL
NEOPLASMS
OF
RECOMMENDATIONS
2. STAGING OF BLADDER CANCER
REFERENCES
14
BLADDER
Bladder Cancer: Epidemiology, Staging
and Grading, and Diagnosis
Z. KIRKALI
T. CHAN, M. MANOHARAN
F. ALGABA, C. BUSCH, L. CHENG, L. KIEMENEY, M. KRIEGMAIR, R. MONTIRONI,
W. MURPHY, I. SESTERHENN, M. TACHIBANA, J. WEIDER
Bladder cancer is a heterogeneous disease with a
variable natural history. At one end of the spectrum,
low grade Ta tumors have a low progression rate and
require initial endoscopic treatment and surveillance,
but rarely present a threat to the patient. At the other
extreme, high grade tumors have a high malignant
potential associated with significant progression and
cancer death rates.
cer, respectively (Figure 2) [1]. The median age at
diagnosis is 65 to 70 years.
Some of the differences between countries are
caused by differences in registration or reporting of
(low grade) pTa tumors. Unfortunately, this makes
the comparison between countries very difficult.
Age-standardized (world) mortality rates vary from
2 to 10 per 100,000 per year for males and 0.5 to 4
per 100,000 per year for females (Figure 3) [2].
The true natural history of untreated noninvasive disease is not fully known. Seventy percent of bladder
tumors present as superficial disease and the rest as
muscle-invasive disease. Among the superficial cancer group, approximately 70% present as Ta lesions,
20% as T1, and 10% as carcinoma in situ (CIS, Tis).
Bladder cancer is 3 to 4 times more common among
males than females. On the other hand, it has been
suggested that the stage-adjusted survival of bladder
cancer among women is worse than among men [3].
The excess of bladder cancer in males is not fully
explained by gender differences in smoking habits
and occupation (the 2 most well-known risk factors
for bladder cancer). Surveys of cancer incidence and
mortality suggest that parous women have a lower
risk of bladder cancer than nulliparous women,
probably due to hormonal changes related to
pregnancy, and that the risk may decrease with
increasing parity [4-7]. Furthermore, in animal
experiments, rats treated with androgenic hormones
developed more bladder tumors than animals treated
with estrogenic hormones [8]. It is therefore suggested that at least some androgenic hormones stimulate
(or do not inhibit) oncogenesis while estrogenic hormones do the opposite.
Many characteristics of urothelial (transitional cell)
carcinoma have been studied in an attempt to predict
the variable tumor behavior. These include pathologic features, cytologic analysis, and molecular markers. Accurate staging and grading of the disease is
important to decide the optimal treatment. An understanding of the epidemiology and bladder screening
strategies helps in the prevention and early detection
of the disease.
I. EPIDEMIOLOGY OF BLADDER
CANCER
1. INCIDENCE AND MORTALITY
For yet undetermined reasons, blacks experience
only half the risk of whites (Figure 4), but the
overall survival among blacks seem to be worse. The
higher incidence among whites compared to blacks
is limited to superficial tumors, with blacks and
whites having a similar risk of more invasive tumors
[9,10] . This suggests that some low stage, low grade
tumors among blacks remain undetected. The higher
risk in whites may also be due to different risk fac-
Bladder cancer is the fourth most common ma-lignancy among Western men, following prostate, lung,
and colon cancer. In Europe and the United States,
bladder cancer accounts for 5% to 10% of all malignancies among males (Figure 1). The risk of developing bladder cancer before the age of 75 years is
2% to 4% for males and 0.5% to 1% for females,
compared to, for example, 8% and 2% for lung can-
15
Figure 1. Age-standardized (World) Incidence Rates (per 100,000) of Bladder Cancer [1]
Figure 2. Cumulative Risk (%) of Bladder Cancer Before the Age of 75 Years [1]
16
Figure 3. Age-standardized (World) Mortality Rates (per 100,000/year) of Bladder Cancer [2]
smoking and respiratory tract cancers.
Although it is well-recognized that cigarette smoking
is the most important risk factor for bladder cancer on
a population basis, additional factors have to play a
role in modifying the risk of smoking-related bladder
cancer. Populations exist with high smoking rates but
low bladder cancer rates (for example, Polynesian
men including native Hawaiians and New Zealand
Maoris) [12]. This suggests differences in the
metabolism of smoking-related carcinogens. For
example, N-acetyltransferase 2 slow acetylators are
known to have a higher risk of bladder cancer from
smoking than rapid acetylators [13]. Exogenous
agents (such as vitamin intake) may modify the susceptibility to smoking-induced bladder cancer as
well.
Figure 4. Bladder Cancer Incidence in the US / 105 Personyears by Race [11]
tors operating in the black and white populations.
Also, racial biologic variations and within-race individual differences may modify various phases of carcinogenesis such as the capacity to convert procarcinogens to carcinogens, to detoxify carcinogens,
and to repair DNA.
All over the world, time trends in bladder cancer follow trends in smoking behavior, comparable to time
trends in lung cancer but with a longer delay. In most
Western communities, bladder cancer incidence and
mortality in men has decreased in the last decade.
2. ENVIRONMENTAL RISK FACTORS
a) Smoking
The most well-established risk factor for bladder
cancer is cigarette smoking (Table 1), although the
association is not as strong as that observed for
b) Occupation
Occupation is the first known and, on a population
17
Excess risks have been frequently observed among
painters, which is thought to be due to exposure to
possible carcinogenic constituents of paints like benzidine, polychlorinated biphenyls, formaldehyde,
and asbestos and solvents like benzene, dioxane, and
methylene chloride [18]. A moderately increased risk
is also found among leather workers and shoe makers, although the responsible agent is still un-known
[19]. The workers are exposed to leather dust, dyes,
and solvents. Therefore, it is imaginable that the earlier mentioned aromatic amines play an important
role.
Table 1. Smoking and Bladder Cancer
• Cigarette smoking increases bladder cancer risk two- to
fourfold
• 30% to 50% of all bladder cancer is caused by cigarette
smoking
• Latency period is approximately 20 to 30 years
• Increasing intensity and/or increasing duration → increasing risk
• Quitting smoking → immediate decreasing risk approaching baseline after 20 to 30 years
• Black tobacco threefold increased risk vs. blond tobacco
An excess risk of bladder cancer is also observed in
aluminum, iron, and steelworkers, which may be the
result of exposure to aromatic amines and polycyclic
aromatic hydrocarbons (PAHs) in coal-tar pitch
volatiles [20-22].
• Unfiltered cigarettes 35% to50% higher risk than filtered
cigarettes
• Deep inhalation 30% to 40% higher risk than no inhalation
• Pipe/cigar smoking → higher risk? (inhalation pattern)
Furthermore, many studies have assessed the relation
between bladder cancer and diesel exhaust exposure,
and evidence is accumulating that diesel exhaust
moderately increases the risk of bladder cancer [23].
Garage mechanics; drivers of trucks, buses, and
cabs; and other maintenance workers in transport
companies appear to have an increased risk of bladder cancer. A positive trend in risk with increasing
duration of employment seems to be present (Table
2).
• Snuff or chewing tobacco → no elevated risk
level, second most important risk factor for bladder
cancer. It has been estimated that occupational exposures may account for as much as 20% of all bladder
cancer [14]. Exposure to beta-naphthylamine, 4aminobiphenyl (ABP), and benzidine, principally
among workers in the textile dye and rubber tire
industries, are the only specific agents that have been
associated with bladder cancer unequivocally. Due to
strict regulations, these specific chemicals are now
banned from the workplace and contribute minimally to the current incidence of bladder cancer in Western countries. However, many other strong candidates for bladder carcinogens still exist such as
ortho-tolui-dine, which is used now in the manufacture of dyes, rubber chemicals, pharmaceuticals, and
pesticides [15]. In fact, many occupations have been
marked as potentially high-risk occupations. As
already pointed out, a strongly increased risk of bladder cancer may still exist for (ex-)workers in the dye,
rubber, and chemical industries, as a result of (historical) exposure to aromatic amines (arylamines)
like benzidine, 2-naphthylamine, 4-ABP, 4,4’methylene-dianiline,
4,4’-methylene-bis
(2chloroaniline), o-toluidine, 4,4’-methylene-bis (2methylaniline), and 4-chloro-o-toluidine [16,17].
The risk of bladder cancer among workers in such
industries should therefore be monitored continuously. If specific plants are suspected, the identification
of the causative agent should be started immediately,
preventive measures should be taken, and exposed
workers may have to be screened for bladder cancer
for at least 2 decades.
Table 2. Motor Exhaust and Bladder Cancer [24]
Duration of Employment
(years)
Cases Controls Odds Ratio
Never any motor exhaustrelated occupation
1353
2724
1.0
<5
74
129
1.2
5-9
32
45
1.4
10-24
33
31
2.1
25+
22
19
2.2
Number adjusted for age and smoking
Exhaust emissions contain PAHs and nitro-PAHs.
The PAHs are formed mainly as a result of pyrolytic
processes, in particular the incomplete combustion
of organic materials. Diesel engines emit at least 10
times more nitro-PAHs than gasoline engines.
Although an increased risk of bladder cancer has
been reported for many other occupations, findings
for most of these occupations are not consistent
[25,26].
18
sure-related variables were the amount of daily tap
water consumption and yearly average trihalomethane concentration. The average trihalomethane levels between the studies varied from
10 to 30 µg/L. An exposure window of 40 years was
defined, extending from 45 to 5 years before the
interview. Exposure to trihalomethanes was associated with an excess risk among ever-exposed men
(odds ratio [OR] 1.32, 95% confidence interval [CI]
1.10 to 1.59). The risk increased with increasing
exposure. Among women, no increased risk was
found. This discrepancy between men and women is
still unclear [40]. It may be due to several mechanisms, for example, the role of sex hormones in the
metabolization of chlorination byproducts [41,42] or
the activity of CYP2E1, which is important in the
metabolism of chloroform to active metabolites, and
appears to be higher in men compared to women [4346].
c) Drinking Water Quality
1. CHLORINATED DRINKING WATER
In the United States and many other countries,
drinking water is disinfected with chlorine. The chlorination is important for the microbiologic safety of
drinking water. During the chlorination process,
chlorine reacts with organics in water resulting in
halogenated organic compounds (mainly trihalomethanes such as chloroform and bromoform).
Bio-assays and in vitro studies suggest that some of
these halogenated compounds are mutagenic or carcinogenic. On the other hand, a recent study from
Australia found that the trihalomethane concentration in chlorinated drinking water was not related to
DNA damage in bladder cells [27].
Several studies have been performed on chlorinated
drinking water and bladder cancer, and all of these
reported increased risks [28-35]. The (smokingadjusted) risks varied from 1.4 to 2.2 for both sexes
combined (exposure time varied from 20 to over 60
years). In most studies, the risks tend to increase with
duration of exposure. Despite these studies, a report
of the International Agency for Research on Cancer
(IARC) from 1999 concluded that there was inadequate evidence that individual chlorination byproducts such as chloroform and other trihalomethanes were carcinogenic [36]. Although
some studies showed an association of chlorinated
drinking water intake with cancer, it was argued that
single compounds could not be evaluated because
these compounds occur in mixtures. A report of the
World Health Organization, published in 2000, concluded that the evidence was insufficient to determine whether observed associations were causal or
to determine which specific byproduct or contaminant plays a role.
In conclusion, exposure to chlorinated drinking
water probably increases the risk of bladder cancer.
Although the observed risks are relatively small, the
attributable risk may be considerable, given the size
of the exposed population.
2. ARSENIC IN DRINKING WATER
Several large studies have evaluated the association
between ingestion of arsenic in drinking water and
the risk of bladder cancer. Most studies have been
performed in Asia and Latin America.
Several studies have been performed in the endemic
area of Taiwan. Between 1930 and the mid-1960s,
the population in this region was exposed to highly
contaminated well water (arsenic levels of 170 to
800 µg/L; current regulation is maximum 10 µg/L).
These studies have shown a clear dose-response relation with bladder cancer. The age- and sex-adjusted
odds ratios of developing bladder, lung, and liver
cancers for those who had used well water for 40 or
more years were 3.9, 3.4, and 2.7, respectively, as
compared with those who never used well water
[47]. In contrast to Taiwan, Bangladesh and West
Bengal experience an ongoing problem with very
high concentrations of arsenic in drinking water that
exceed in some sources 2000 to 4000 µg/L [48].
Arsenic levels in drinking water in the United States
and Europe are much lower than reported in Taiwan.
A recent case-control study by Steinmaus et al. included 7 counties in the Western United States in
which the levels of arsenic in drinking water vary
from 10 to 100 µg/L [49]. All odds ratios were near
1.0 when an exposure window of 5 to 20 years was
In 2004, Villanueva and colleagues reported a pooled
analysis in which primary data from 6 case-control
studies with individual-based exposure assessments
were pooled [37]. These studies were conducted in 5
countries (Italy [unpublished data 2003], Canada,
Finland, USA, and France) using trihalomethanes as
a marker for the total mixture of chlorination byproducts [29,31,32,38,39]. Exposure information and
covariates were extracted from the original databases including age, sex, smoking, occupation, coffee,
fluid consumption, and socioeconomic status. The
final pooled dataset comprised 3419 cases and 6077
controls. All cases were histologically confirmed. All
studies followed similar approaches to estimate the
trihalomethane levels in the water source. The expo-
19
epithelium. Most cyclophosphamide-induced tumors
present themselves as muscle-infiltrating lesions at
the time of diagnosis with a relatively short latency
period (6-13 years). It is unclear whether cyclophosphamide-induced urothelial malignancies are due to
its immunosuppressive or inherent carcinogenic
properties, but it is likely that the 2 factors work
together. Of 4 known metabolites of cyclophosphamide, acrolein and phosphamide mustard have
been demonstrated to bind to DNA, and acrolein is
known to be responsible for its bladder toxicity.
defined. When an exposure window of 40 years or
more was used, increased odds ratios were found for
arsenic intakes greater than 80 µg/day, although none
were statistically significant. Overall, no clear association is found between low to intermediate exposure to arsenic in drinking water and the risk of bladder cancer.
d) Medical History
1. CHRONIC URINARY TRACT INFECTION
Chronic urinary tract infection is associated with the
development of bladder cancer, especially invasive
squamous cell carcinoma [50]. This type of cancer
may occur in patients with spinal cord injury in
whom chronic cystitis is inevitable. This may be the
result of formation of nitrites and nitrosamines by
bacterial flora and/or the inflammatory process,
which leads to an increased cell proliferation, providing more opportunities for spontaneous genetic
mistakes.
4. RADIOTHERAPY
Radiotherapy is also a known risk factor for bladder
cancer. Kaldor et al. carried out a case-control study
of tumors of the bladder in women who had previously been treated for ovarian cancer [54]. The risk
of bladder tumors was increased for patients who had
been treated with radiotherapy or chemotherapy
(thiotepa and melphalan) compared to patients
treated with surgery. Moreover, the risk seemed to be
much higher in patients who received both.
2. PHENACETIN
Heavy consumption of phenacetin-containing analgesics (not sold anymore) increases the risk of upper
urinary tract cancer, but has only a marginal effect on
bladder cancer risk [51,52].
e) Schistosomiasis
Squamous cell carcinoma of the urinary bladder has
been known to be associated with Schistosoma
haematobium infection for many years. The epidemio-logic association is based both on case-control studies and on the close correlation of bladder
cancer incidence with the prevalence of S. haematobium infection within different geographic areas [5558]. S. haematobium is found throughout much of
Africa and the Middle East. The life cycle of S.
haematobium requires waterborne transmission of
infection between man and snail. Water becomes
contami-nated by Schistosoma eggs when people
urinate in the water. The eggs release larval forms
(miracidia) that have to penetrate appropriate snail
hosts within 16 to 32 hours. Inside the snail, the larvae will grow and develop into cercariae over 6
weeks. After this period, the cercariae leave the snail
and are able to survive in water for 2 to 3 days. In
this period, the parasites have to find a human host
and penetrate the skin by mechanical action and
enzymatic secretions of the cephalic glands. The parasites migrate by the blood vessels where they
mature to male and female worms. These mate and
travel to the vesical veins to deposit eggs in the bladder wall. Finally, the eggs are extruded into the urine
(Figure 6).
3. CYCLOPHOSPHAMIDE
Cyclophosphamide, an alkylating agent used in the
treatment of malignant neoplasms, particularly lymphoproliferative and myeloproliferative diseases,
increases the risk of bladder cancer (mainly urothelial carcinoma) with a clear dose-response relationship (Figure 5).
Cyclophosphamide is acutely toxic to the bladder
mucosa and produces cellular abnormalities in the
<0.5 Gy
≥ 0.5 Gy
Figure 5. Risk of Bladder Cancer According to Cumulative Dose of Cyclophosphamide and Administration of
Radiotherapy [53]
It is not the worms but the eggs that cause the disease in humans; the egg deposit causes a response
that results in cystitis and hematuria. Over time, the
20
ingly, large intervention trials did not find clear protective effects of antioxidants. The Physicians’
Health Study (PHS), involving 22 000 male physicians in the United States, and the Alpha-Tocopherol,
Beta-Carotene Cancer Prevention Study (ATBC
cohort study), involving 29 000 Finnish male smokers, investigated supplements of antioxidant nutrients in different doses and combinations and produced surprising results [64,65]. One arm of the
ATBC cohort study involved daily supplementation
with beta-carotene and, after 5 to 8 years of supplementation, an unexpected 18% higher incidence of
lung cancer and an 8% higher overall mortality was
found. In the PHS, no effect of beta-carotene on disease and death was observed. Concerning alphatocopherol, a 34% lower incidence of prostate cancer, but no effect on lung cancer, was found in the
ATBC cohort study.
During the follow-up period of the ATBC cohort
study, 344 men developed bladder cancer. Consumption of fruits and vegetables was not associated with
the risk of bladder cancer [66]. Similarly, no associations were observed for specific groups of fruits or
vegetables. Dietary intake of alpha-carotene; betacarotene; lycopene; lutein/zeaxanthin; beta-cryptoxanthin; vitamins A, E, and C; and folate were not
related to the risk of bladder cancer. This study suggests that fruit and vegetable intakes are not likely to
be associated with bladder cancer risk. However, in
a meta-analysis by Steinmaus et al., a risk of 1.4
(95% CI 1.08 to 1.83) was found for a diet low in
fruit intake [67].
Figure 6. Life Cycle and Geographic Distribution of Schistosoma haematobium [61]
chronic inflammatory response from schistosomiasis
leads to changes in the urothelium resulting in squamous metaplasia of the epithelium. Individuals with
chronic schistosomiasis may eventually develop
squamous cell carcinoma, probably as a result of a
higher amount of carcinogenic nitroso compounds in
the urine and/or a depressed immunocompetence of
infected patients [59,60].
Evidence for an increase in bladder cancer risk
because of a high total fat intake is insufficient. The
same holds for the relation with diets high in cholesterol or saturated (animal) fat. People with a high intake of fried food were found to have 2 to 3 times the
risk of bladder cancer than people who did not consume fried foods. Although this association was
found in several studies, evidence remains insufficient.
f) Diet
In observational studies, high vegetable and fruit
consumption has been associated with a decrease in
the risk of almost all cancers including bladder,
although several large cohort studies report no protective effect [62,63]. A role of diet and nutrition in
bladder carcinogenesis is plausible since most substances and metabolites (including precarcinogens)
are excreted by the urinary tract. A possible biologic
mechanism is that several antioxidants (vitamins A,
C, and E; retinol; selenium; and folate) detoxify free
radicals and thereby decrease cancer risk. Surpris-
Fairly convincing evidence exists with regard to a
risk-increasing effect of food pyrolysis products
(mutagenic and carcinogenic heterocyclic amines),
which are formed during cooking, broiling, grilling,
or barbecuing of meat and fish.
1. ALCOHOL
Although consumption of low levels of alcohol (1 or
2 drinks a day) is believed to reduce cardiovascular
disease, positive associations have been reported
with the risk of several types of cancer (such as oral
21
man. In studies among diabetics in the United States
and United Kingdom who have substantial use of
artificial sweeteners, no elevated bladder cancer
mortality rates were found [73]. In a study by
Takayama et al., 20 monkeys were treated with sodium saccharine (5-10 times the daily intake for
humans) for 5 days a week from 24 hours after birth
until the age of 24 years [74]. Sixteen monkeys
served as controls. No evidence was found of formation of solid material (crystals) in the urine, providing additional evidence that sodium saccharine has
no carcinogenic effect on the primate urinary tract.
The most recent study among humans on this subject
was conducted by Sturgeon et al [75]. Bladder cancer patients (1860) and controls (3934) were
grouped into low (<1.68 mg/day) and high (>1.68
mg/day) sweetener consumption. High consumption
of sweeteners was correlated with a modest
increased risk of developing bladder cancer (OR 1.3,
95% CI 0.9 to 2.1).
cavity and pharynx, larynx, liver, esophagus, colon,
and breast). Alcohol consumption has often been
studied as a possible risk factor for bladder cancer.
The results are not consistent but point in the direction of no association. For example, in a large study
among Danish brewery workers with a very high
average beer intake of 2 to 2.5 liters/day, no elevated
risk was found [68]. The positive findings in some
studies may be the result of residual confounding by
smoking (several case control studies did not adjust
for smoking habits) or chance.
2. COFFEE
Similar to the above mentioned association, coffee
and the risk of bladder cancer has often been studied
but the results are very inconsistent, although
pointing in the direction of a weak positive association. In the United States bladder cancer study with
2982 cases and 5782 controls, the largest populationbased case-control study on bladder cancer, the risk
for ever versus never coffee drinkers (adjusted for
age, race, geographical area, and tobacco consumption) was found to be 1.6 (95% CI 1.2 to 2.2) for
males and 1.3 (95% CI 0.8 to 1.7) for females [69].
However, in a Danish study no elevated risk was
found for coffee drinking and bladder cancer, though
in Scandinavian countries coffee consumption is
about 2.5 times as high as in the United States [70].
In a recent pooled analysis of several case-control
studies in Europe, 564 cases and 2929 controls were
included who had never smoked [71]. No excess risk
was found in ever versus never coffee drinkers. For
coffee drinkers with more than 10 cups per day, an
increased risk was found in both men and women
(OR 1.0; 95% CI 1.0 to 3.3).
4. TOTAL FLUID CONSUMPTION
Several observational studies have assessed the relationship between total fluid intake and the risk of
bladder cancer, but the results of these studies are
very inconsistent. Positive, negative, and no association have been reported [28,76-78].
g) Hair Dyes
The risk of bladder cancer through the use of hair
coloring products has been studied since the late
1970s but received more interest in the last few
years. Hair dyes are widely used in Western communities. It is estimated that more than one-third of
women above the age of 18 and more than 10% of
men above the age of 40 use some type of hair dye.
Some hair dyes contain aromatic amines such as 4aminobiphenyl, of which small amounts may be
absorbed percutaneously [79]. The levels of suspected carcinogens differ between the different types
of dyes (permanent, semi-permanent, and temporary
rinse dyes) and between the different colors. Occupational exposure to hair dyes by hairdressers is
believed to moderately increase the risk of bladder
cancer (combined analysis of studies yielded OR
1.4) [80]. Since the publication of a study in 2001,
the personal use of hair dyes has received much
attention. After 2 cohort studies from the United
States (the Nurses Health Study and the American
Cancer Society CSP-II study) did not find an association between personal use of permanent dyes and
bladder cancer, Gago-Dominguez and colleagues
reported a case-control study from Los Angeles that
involved almost 900 incident cases of bladder cancer
Most inconsistencies in the reported data are probably due to the effect of residual confounding by
smoking or by other correlates of coffee drinking.
Because coffee drinking and smoking are strongly
correlated, an incomplete controlling of smoking
(because of misclassification of smoking habits) can
result in an apparent relation of coffee drinking and
bladder cancer. Another, more theoretical, possibility
is that people with a relatively high bladder cancer
risk (slow acetylators) drink more coffee [72].
3. ARTIFICIAL SWEETENERS
No consistent positive association between bladder
cancer risk and the use of artificial sweeteners (like
saccharine and cyclamate) has been found, although
animal models (rats) suggested a strong relation.
This may be due to the fact that the specific biologic
mechanism in some animal models does not exist in
22
3. GENETIC SUSCEPTIBILITY
and an equal number of age-, sex-, neighborhood-,
and ethnicity-matched controls [81-83]. Overall, regular use of hair dyes did not increase the risk of bladder cancer. However, women who used permanent
hair dyes at least once a month experienced a
cigarette-smoking adjusted 2.1-fold risk of bladder
cancer relative to non-users. The use of this type of
hair dye among men was too rare (about 2% among
controls) for meaningful analyses. Semi-permanent
and temporary dyes did not increase the risk of bladder cancer. In further analyses, women who used
these types of dyes were combined with the nonusers. The relative risk of permanent dyes among
women showed dose-response relationships with
duration of use, frequency of use, and cumulative
number of times used over lifetime [83]. In response
to this study, 1 of the 2 earlier studies with negative
results, the American Cancer Society CSP-II study,
published an update. After 16 years of follow-up of a
cohort of more than 500 000 women, the death rate
of bladder cancer among women (N=336) was not
related to the use of permanent hair dyes. Even
among women who used these dyes for more than 20
years, the relative risk for bladder cancer mortality
was not increased [84].
a) Gene-Environment Interactions
The Los Angeles County bladder cancer study on
hair dyes and bladder cancer is a good example of
the possible modifying role of constitution on the
effect of environmental or lifestyle factors [87].
Although many environmental risk factors have been
implicated in the etiology of bladder cancer, only
occupation and smoking are responsible for a considerable part of all new cases. Without any doubt,
genetic susceptibility will prove to be responsible for
another considerable part, most importantly by geneenvironment interactions. Most environmental carcinogens are activated inside the body into reactive
oxygenated intermediates (which may interact with
DNA) by phase I enzymes. Subsequently, these reactive intermediates are detoxified into conjugated
water-soluble products by phase II enzymes. For
example, oxidation of arylamines in the liver by
cytochrome P450 1A2 leads to N-hydroxylated
metabolites. These may enter the circulation and
react covalently with hemoglobin in erythrocytes.
After filtration into the bladder lumen the metabolites may react with urothelial nucleic acids (Figure
7). Detoxification of the reactive metabolites into
non-carcinogenic N-acetylated arylamides may take
In a case-control study from New Hampshire, including 98 women with bladder cancer and 238 controls, the use of permanent hair dyes was associated
with a 1.5-fold increased risk of bladder cancer.
However, the use of rinse dyes was associated with
an increased risk as well (OR 1.7). Both associations
were not statistically significant and clear doseresponse effects were not observed [85]. The different results between these studies are difficult to
explain. At the end of 2001, Gago-Dominguez et al.
reported an additional analysis of their data. They
phenotyped 61% of the female cases and 60% of the
controls for N-acetyltransferase, an important enzyme in the detoxification of aromatic amines.
They found that the increased risk of the use of permanent hair dyes was restricted to N-acetyltransferase 2 slow acetylators [86]. Recently, this study was
extended with the genotyping of GSTM1, GSTT1,
GSTP1, and NAT1, and the phenotyping of NAT2
and CYP1A2. Again, it was demonstrated that differences in arylamine activation and detoxification
pathways (especially NAT2, NAT1, and CYP1A2)
modify the relationship between permanent hair dyes
and bladder cancer in women [87]. These findings
support a causal role of permanent hair dyes but
leave the discrepancy with earlier studies unanswered.
Figure 7. Biochemical Pathway for Urinary Bladder Cancer Induction by Aromatic Amines [88]
23
place by N-acetylation, which is catalyzed by the Nacetyltransferases, preferentially by NAT2 in the
liver and by NAT1 in skin cells.
have been reported. It is too early, however, to assess
the relevance of these findings. Again, inconsistent
results, potential (or perhaps even probable) publication bias, and the absence of validation studies suggest that false positive findings are a real problem.
This research area would benefit greatly from international collaborations where large-scale projects
study the role of many polymorphisms simultaneously using high-throughput array technology, while
validating the findings in collaborative
projects. The present non-standardized study-bystudy and gene-by-gene approach will only lead to a
lot of confusion. Furthermore, perhaps the most
important aim of studies on gene polymorphisms
should be to identify subgroups in which environmental risk factors can be evaluated with increased
power. It is therefore advised to give as much
emphasis with data collection on hypothesized environmental risk factors as on genetic polymorphisms.
The genes that code for these enzymes show
interindividual variability leading to differences in
catalytic activity. Most of this variability comes from
single nucleotide polymorphisms (SNPs) and tandem repeats, but small homozygous deletions in specific genes may even lead to a total absence of
enzyme activity. Numerous studies have examined
the role of metabolic gene polymorphisms in the
development of bladder cancer. Genes that have been
studied include NAT1, NAT2, GSTM1, GSTT1,
GSTP1, CYP1A1, CYP1A2, CYP1B1, CYP2D6,
CYP2E1, CYP3E4, ADH3, NQO1, SULT1A1,
MPO, COMT, and MnSOD. The role of NAT2 slow
acetylation phenotype or genotype and bladder cancer is most frequently studied. In a meta-analysis of
22 studies, it appeared that slow acetylators have a
40% (95% CI 1.2 to 1.6) increased risk of bladder
cancer. This increased risk, however, may be different in different populations (higher in Asians and
lower or even absent in United States Caucasians)
[13].
b) Familial Bladder Cancer
Urothelial carcinoma of the ureter and renal pelvis is
known to be part of the Hereditary Non-polyposis
Colon Cancer (HNPCC) syndrome, which is caused
by mutations in DNA mismatch repair genes. For yet
unknown reasons, urothelial carcinoma of the bladder is not part of this syndrome [91]. In fact, familial
bladder cancer is a fairly rare phenomenon compared
to the familial occurrence of many other tumor sites.
Nevertheless, numerous case reports describe fa-milial clustering of urothelial carcinoma. Several
demonstrate an extremely early age at onset, suggesting a genetic component [92]. Only a few epidemiological studies specifically addressed familial
bladder cancer. Goldgar and colleagues studied the
risk of cancer in first-degree relatives of cancer
probands, yielding an increased risk for bladder cancer among first-degree relatives of 1.5 (95% CI 1.0
to 2.2) [93]. When only young probands (age < 60
years) were considered, the familial risk was 5.1
(95% CI 1.0 to 12.5). In a study from New York,
demographic data and cigarette smoking status on all
the first degree relatives of 319 male bladder cancer
cases and 319 neighborhood controls were collected.
The cohorts were linked to the cancer registry,
yielding an almost twofold risk (hazard ratio [HR]
1.9, 90% CI 0.9 to 4.1) of bladder cancer for firstdegree relatives [94]. By contrast, a comparable
study among the population of Iceland reported only
a slightly elevated risk of urothelial carcinoma
among relatives of 190 bladder cancer patients with
an observed-to-expected ratio of only 1.2 (95% CI
0.9 to 1.7) [95]. The largest study on familial bladder
The phase II glutathione-S-transferases are classified
into at least 4 genetically distinct classes of enzymes
(alpha, theta, mu, and pi), which conjugate reactive
entities with glutathione. In humans, mu and theta
class of GST isoenzymes, GSTM1 and GSTT1 display different phenotypes due to deletions of the
genes. GSTM1 is highly efficient in conjugating aryl
epoxides, which are formed by phase I cytochrome
P450 enzymes after exposure to certain PAHs.
GSTM1 may also detoxify aromatic amines. Enzyme
activity is found in several organ systems such as the
liver and bowel, in lymphocytes, and also in the
bladder endothelium. GSTM1 activity is absent in
approximately 40% of the Western population
because of a homozygous deletion of the GSTM1
locus on chromosome 1p13 [89]. In a meta-analysis
of 17 studies, a lack of GSTM1 activity was associated with bladder cancer with an odds ratio of 1.44
(95% CI 1.23 to 1.68) [90]. For specific variants in
most other metabolic genes that were studied until
now, the results are fairly inconsistent or were reported in 1 study only.
Recently, attention has also been paid to polymorphisms in genes with other functions, such as DNA
repair, cell cycle control, immune response, folate
metabolism, and cell adhesion (for example XRCC1,
XPD, XRCC3, CDH1, TP53, TNF, HER-2, HRAS1,
CCND1, MTHFR, and MS). Many positive findings
24
also evaluated among the relatives of probands with
a positive family history of urothelial carcinoma.
There was some suggestion (nonsignificant) of a
clustering of tumors of the female genital organs,
non-urothelial urinary tract tumors, and cancer of the
hematolymphopoietic system [96].
cancer was conducted by the same group but in the
Netherlands. Using a family case-control design,
1193 patients newly diagnosed with urothelial carcinoma of the bladder, ureter, renal pelvis, or urethra
were contacted. Information on the patients’ firstdegree relatives was collected by postal questionnaire and subsequent telephone calls. The patients’
partners filled out a similar questionnaire on their
relatives. All reported occurrences of urothelial carcinoma among the 8014 first-degree case-relatives
and 5673 control-relatives were verified using medical records. Disease occurrence among case-relatives
and control-relatives was compared with random
effect proportional hazards regression analyses while
adjusting for age, sex, and smoking behavior. Among
the case-relatives, 101 individuals were diagnosed
with cancer of the bladder (97), ureter (3), and renal
pelvis (1), compared to 38 individuals among the
control-relatives (bladder 36, ureter 1, and urethra 1).
In 6 case-families and 2 control-families, 2 affected
first-degree relatives were found. Overall, 8% of the
patients had a positive family history of urothelial
carcinoma compared to 4% of the controls. The
mean age at diagnosis of patients with a positive
family history was similar to that of patients with a
negative family history (62 years). The mean age at
diagnosis of urothelial carcinoma among affected
case-relatives was only slightly lower than that of
affected control-relatives (64 vs. 66 years). The
cumulative risk of urothelial carcinoma among caserelatives was 3.8% compared to 2.1% among control-relatives. The age- sex-, and smoking-adjusted
hazard ratio of urothelial carcinoma for case-relatives compared to control-relatives was 1.8 (95% CI
1.3 to 2.7). This risk appeared to be higher among
women (HR 3.2) and among nonsmokers (HR 3.9).
When only parents were included in the analyses, the
hazard ratio increased to 2.2, while it decreased to
1.5 when only siblings were included. After stratification by tumor site in the probands (upper vs. lower
urinary tract), the adjusted HR was 1.8 among relatives of probands with upper urinary tract urothelial
carcinoma and 1.9 among relatives of probands with
bladder urothelial carcinoma. When all the relatives
of probands with a pTa tumor were excluded from
the analyses, the HR increased only slightly to 2.0.
The same was found when the relatives of probands
older than 60 years were excluded from the analyses
(HR 2.4). A striking clustering of tumors at other
sites among the case-relatives was not found
although an increased risk was observed for tumors
of the hematolymphopoietic system (HR 1.9, 95% CI
1.2 to 3.0). Familial clustering with other tumors was
From these epidemiological studies, it can be concluded that the risk of bladder cancer is increased
approximately twofold with a positive family history
of bladder cancer. The next question is whether this
is caused by genetic susceptibility or shared environment. In a twin study from Scandinavia (Denmark,
Sweden, and Finland), Lichtenstein et al. reported 5
concordant and 146 discordant pairs of bladder cancers among 7231 monozygotic male twin pairs.
Among 13 769 dizygotic male twin pairs, 2 concordant pairs and 253 discordant pairs were found. The
relative risk of bladder cancer among monozygotic
twins was 6.6 (95% CI 2.6 to 16.9). The relative risk
among dizygotic twins was 1.7 (95% CI 0.4 to 6.9).
The concordance rate was 3 times higher among
monozygotic twins (6%) than among dizygotic twins
(2%). Assuming that the correlation in environmental risk factors is similar among monozygotic and
dizygotic twins, this finding suggests the existence
of a genetic etiology of bladder cancer [97]. In a
study on the Swedish Family-Cancer Database, it
was estimated that 7% of the occurrence of bladder
cancer is due to genetic effects, 12% to shared environmental effects, 4% to childhood environmental
effects, and 77% to nonshared environmental effects
[98].
The group from the Netherlands evaluated whether
mutagen sensitivity plays a role in developing
urothelial carcinoma and whether this sensitivity is
different in familial and nonfamilial cases. Intrinsic
susceptibility was quantified by a mutagen sensitivity assay (mean number of chromatid breaks per cell
(PBLs) after damage induction with bleomycin in the
late S-G2 phase of the cell cycle). Twenty-five sporadic patients, 23 familial patients (2 patients in 1
nuclear family), and 13 hereditary patients (2
patients < 60 years or 3 patients in 1 nuclear family)
were selected and compared with control subjects
without a history of cancer. Patients with urothelial
carcinoma showed a higher mutagen sensitivity
score compared to control subjects (mean number of
chromatid breaks per cell 0.91, 95% CI 0.84 to 0.97,
and 0.74, 95% CI 0.69 to 0.79, respectively; P =
0.001), suggesting a genetic origin [99].
Recently, a new bladder cancer gene was discovered
by the collaborative group of Schoenberg and
25
Sidransky at Johns Hopkins in Baltimore [100]. In
1996, this group identified a family in which a male
was diagnosed with grade 2 superficial urothelial
carcinoma of the bladder at the age of 29 years. He
subsequently developed renal pelvis carcinoma. His
mother died of metastatic urothelial carcinoma of the
bladder at the age of 65. Because both the proband’s
wife and his mother had a history of miscarriages, a
karyogram was made which showed a balanced
germline translocation t(5;20)(p15;q11) [101]. Dr.
Sidransky’s lab zoomed in at the breakpoints of this
translocation, which finally resulted in the discovery
of a new bladder cancer gene at 20q11 [100]. This
gene, CDC91L1, encoding CDC91L1, which is also
called phosphatidylinositol glycan class U (PIG-U),
has a role in the glycosylphosphatidylinositol (GPI)
anchoring pathway. Further research suggested that
the gene is amplified and overexpressed in as many
as one-third of bladder cancers and primary tumors.
CDC91L1 should therefore be regarded as an oncogene. The translocation led to overexpression of the
gene and, probably, to both bladder cancers in this
pedigree. Carriers of the translocation in this family
were therefore genetically susceptible for bladder
cancer. Because the exact translocation site should
be regarded as an extremely rare phenomenon, this
gene should not be considered as a candidate for the
genetic cause of many patients with hereditary bladder cancer. For that, tumor suppressor or DNA mismatch repair genes have yet to be discovered.
Recently, it was shown that inherited mutations in
the retinoblastoma tumor suppressor gene may cause
bladder cancer. In a long-term follow-up study from
the UK, 5 bladder cancer cases were found among
144 hereditary retinoblastoma cases, an observed to
expected ratio of 26.3 (95% CI 8.5 to 61.4) [102].
This study shows that bladder cancer should be put
on the list of tumors for which hereditary retinoblastoma patients should be checked during lifetime follow-up.
superficial disease and to the risk of metastases and
death in invasive disease. Surprisingly, little attention has been paid to the role of lifestyle and constitution on prognosis. With the current knowledge, it is
impossible for clinicians to advise patients about the
prognostic benefit of lifestyle changes. Bladder cancer prognosis is related to age (younger patients having a better prognosis), gender (males having a better prognosis), and race (whites having a better prognosis), but all of these differences can be largely
explained by a different stage at diagnosis.
4. LIFESTYLE AND PROGNOSIS
1. CLASSIFICATION OF UROTHELIAL
NEOPLASMS
In a systematic review by Aveyard et al., 15 studies
were identified in which the prognostic role of smoking and stopping smoking was reported [103]. Overall, the results suggested that continued smoking or a
lifetime of smoking constitutes a moderate risk f
actor for recurrence and death. Also, stopping smoking probably results in a clinically relevant prognostic improvement. Unfortunately, most of the studies
had major methodological shortcomings. Firm evidence-based conclusions can therefore not be drawn.
In a study from Japan of 258 patients, drinking of
alcoholic beverages was significantly associated
with a better survival (HR 0.46, 95% CI 0.3 to 0.8),
but a clear dose-response relationship was not
observed. No prognostic significance was found for
the use of artificial sweeteners, coffee, powdered
green tea, and cola consumption [104]. Without any
doubt, a large body of data still exists from studies on
the etiology of bladder cancer. These data may be
supplemented quite easily with follow-up data in
order to learn more about the prognostic value of
lifestyle. Also, future epidemiological studies should
consider the collection of follow-up data for this purpose.
II. STAGING AND GRADING OF
BLADDER CANCER
Although much research has been done and is still
ongoing on prognostic factors in invasive and superficial bladder cancer (such as angiogenesis, cell
cycle control proteins, and cell adhesion molecules)
the management of patients is usually based on clinical characteristics only (such as tumor stage, grade,
and lymph node involvement). Based on these
characteristics, it appears to be very difficult to predict prognosis on an individual level. This applies
both to the risks of recurrence and progression in
In December 1998, members of the World Health
Organization (WHO) and the International Society
of Urologic Pathologists (ISUP) published the
WHO/ISUP consensus classification of urothelial
(transitional cell) neoplasms of the urinary bladder
(Level 4, [105]). This new classification system arose
out of the need to develop a universally acceptable
classification system for bladder neoplasia that could
be used effectively by pathologists, urologists, and
26
Dysplasia (intraurothelial neoplasia) was defined as
a lesion with appreciable cytologic and architectural
abnormalities felt to be neoplastic, yet falling short
of the diagnostic threshold for carcinoma in situ.
There is evidence along several lines of investigation
that dysplasia may be a precursor of invasive carcinoma (108-111, Level 3; 112, Level 2; 113, Level 3).
oncologists. Prior to this classification system,
numerous diverse grading schemes for bladder cancer existed whereby the same lesion seen by different pathologists would result in very different diagnoses solely based on definitional differences of
lesions. Another strength of the consensus classification system is that it provides detailed histological
criteria for papillary urothelial lesions. In contrast,
prior grading systems for bladder tumors were vague
and subjective. This classification system not only
covered neoplastic conditions, but also the nomenclature of preneoplastic lesions .
CIS is a flat lesion of the urothelium, and documented precursor of invasive cancer in many cases
(Figure 8A). Prior to the consensus classification,
CIS was frequently underdiagnosed and described as
moderate dysplasia or atypia. The WHO/ISUP system described the key histologic features of CIS,
including its more subtle variations that were often
underrecognized. Under the WHO/ISUP system, all
CIS are by definition high grade lesions.
a) Normal and Hyperplastic Urothelium
Many pathologists overuse the diagnosis of “mild
dysplasia” to describe flat lesions with minimally
disordered growth pattern or cellular hyperchromasia due to variation in tissue fixation, staining, or
specimen orientation. The consensus classification
states that the term “mild dysplasia” should not be
used and that flat lesions with minimal cytologic atypia and architectural disorder should be diagnosed
as “normal.”
Flat urothelial hyperplasia consists of a markedly
thickened mucosa without cytologic atypia, and may
be seen adjacent to low grade papillary urothelial
neoplasms, but there is no data as to its premalignant
potential when seen by itself.
Papillary urothelial hyperplasia is characterized by
urothelium of variable thickness with undulating
growth. In contrast to papillary urothelial tumors,
these lesions lack distinct fibrovascular cores. Papillary urothelial hyperplasia without cytologic atypia,
because of its frequent association with either a prior
or concurrent history of a low grade papillary bladder neoplasm, is thought to be a precursor lesion of
these neoplasms (Level 3, [106]). Papillary urothelial
hyperplasia may also be lined by cytologically atypical urothelium ranging from dysplasia to flat CIS,
which are often associated with and thought to be a
precursor of high grade papillary urothelial carcinomas (Level 3, [107]).
Figure 8A. Flat Urothelial Carcinoma in Situ
c) Papillary Urothelial Neoplasms: Classification
The classification of papillary urothelial neoplasms
has been a long-standing source of controversy
(Level 4, [114]). One source of controversy lies in
the grading of papillary urothelial carcinomas.
There are numerous grading systems, all of which
have poor interobserver reproducibility, with most
cases falling into the intermediate category (115,
Level 4; 116, Level 2; 117, Level 4; 118,119, Level 3;
120, Level 2; 121, Level 3; 122, Level 2). The
WHO/ISUP system is a modified version of the
scheme proposed by Malmström et al. [120]. A
major limitation of the WHO 1973 grading system is
the vague definition and lack of specific histological
criteria of the various grades. The following statement is the sole description of the difference between
WHO grades 1, 2, and 3, as written in the original
WHO 1973 book: “Grade 1 tumors have the least
b) Flat Lesions With Atypia
Prior to the consensus classification, different pathologists variably used the terms “atypia” and “dysplasia” to denote either inflammatory atypia or a preneoplastic condition. The WHO/ISUP system
described the histological findings associated with
inflammatory atypia and designated these lesions as
“reactive atypia,” which should not be considered
neoplastic.
27
degree of anaplasia compatible with the diagnosis of
malignancy. Grade 3 applies to tumors with the most
severe degrees of cellular anaplasia, and Grade 2 lies
in between” [117]. Detailed histological description
of the various grades, employing specific cytologic
and architectural criteria is one of the major contributions of the WHO/ISUP system. These criteria are
based on the architectural features of the papillae and
the overall organization of the cells. Cytologic features encompassed in the WHO/ISUP system include nuclear size, nuclear shape, chromatin content,
nucleoli, mitoses, and umbrella cells. The terminology used in the WHO/ISUP system parallels that
used in urine cytology. Having a consensus classification between cytology and histopathology is also
advantageous. A website (www. pathology. jhu. edu/
bladder) illustrating examples of the various grades
was developed to further improved accuracy in using
the WHO/ISUP system.
very restrictive criteria for the diagnosis of urothelial
papilloma, in part based on the number of cell layers,
and regarded all other papillary neoplasms as carcinomas. Others applied a broader definition of
“urothelial papilloma” so as not to label all patients
with papillary lesions with minimal cytologic and
architectural atypia as having carcinoma. The
WHO/ISUP system has very restrictive histologic
features for the diagnosis of papilloma, where normal appearing urothelium lines papillary fronds.
Defined as such, it is a rare benign condition typically occurring as a small, isolated growth seen primarily in younger patients. The majority of these lesions
once excised will not recur (Level 3, [123]).
3. PAPILLARY UROTHELIAL NEOPLASMS OF LOW
MALIGNANT POTENTIAL (PUNLMP)
The category of PUNLMP was derived to describe
lesions that do not have cytologic features of ma-lignancy, yet have thickened urothelium as compared to
papilloma (Figure 8B). There is no or very little
1. RELATION OF WHO 1973 TO WHO/ISUP
A major misconception is that there is a one-to-one
translation between the WHO/ISUP and the WHO
1973 classification systems. Only at the extremes of
grades in the WHO 1973 classification, does this correlation hold true. Lesions called papilloma in the
WHO classification system would also be called
papilloma in the WHO/ISUP system. At the other
end of the grading extreme, lesions called WHO
grade 3 are by definition high grade carcinoma in the
WHO/ISUP system. However, for WHO grades 1
and 2, there is no direct translation to the WHO/ISUP
system. Some lesions classified as WHO grade 1 in
the 1973 system that upon review show no cytologic
atypia, some nuclear enlargement, and merely thickened urothelium are papillary urothelial neoplasms
of low malignant potential (PUNLMP) in the
WHO/ISUP system. However, other WHO grade 1
lesions showing slight cytologic atypia and mitoses
are diagnosed in the WHO/ISUP system as low grade
papillary urothelial carcinomas. WHO grade 2 is a
very broad category. It includes lesions that are relatively bland, which in some places are diagnosed as
WHO grade 1 to 2; these lesions in the WHO/ISUP
system would be called low grade papillary urothelial carcinoma. In other cases, WHO grade 2 lesions
border on higher grade lesions, which in many institutions are called WHO grade 2 to 3; these lesions in
the WHO/ISUP classification system would be
called high grade papillary urothelial carcinoma.
2. PAPILLOMA
Figure 8B. Papillary Urothelial Neoplasm of Low
Malignant Potential (PUNLMP)
Using the WHO 1973 system, some experts applied
28
4. LOW AND HIGH GRADE PAPILLARY CARCINOMA
variation of nuclear features or the pattern of organization. Having a category of PUNLMP avoids labeling a patient as having cancer with its psychosocial
and financial (i.e., insurance) implications, although
they are not diagnosed as having a benign lesion
(i.e., papilloma), whereby they might not be followed as closely. The prognosis of these lesions and
other papillary tumors in the WHO/ISUP system will
be discussed later in this work. The current classification system allows for designation of a lesion (papillary urothelial neoplasm of low malignant potential), that biologically has a very low risk of progression, yet is not entirely benign. In the past, these
lesions were a source of controversy, as some experts
would label such lesions as malignant, while others,
not wanting to label a patient with such a low grade
papillary lesion as having carcinoma, would diagnose these lesions as papilloma. This inter-mediate
category allows both schools of thought to diagnose
a lesion as not fully malignant, yet still documents
need for additional follow-up.
Figure 8C1. Papillary Carcinoma, Low Grade
In an attempt to simplify the WHO 1973 system and
avoid an intermediate cancer grade group (WHO
grade 2), which is often the default diagnosis for
many pathologists, the WHO/ISUP system classifies
papillary urothelial carcinoma into only 2 grades.
Low grade papillary urothelial carcinoma exhibits an
overall orderly appearance but has minimal variability in architecture and/or cytologic features, which
are easily recognizable at scanning magnification
(Figure 8C 1&2). High grade papillary urothelial
carcinomas are characterized by a disorderly appearance due to marked architectural and cytologic
abnormalities, recognizable at low magnification
(Figure 8D). It is important to remember that a single papillary urothelial neoplasm may contain a
spectrum of cytologic and architectural abnormalities. In tumors with variable histology, the tumor
should be graded according to the highest grade,
although current practice is to ignore minuscule
Figure 8C2. Papillary Carcinoma, Low Grade
29
risk of recurrence, progression, and death from bladder cancer. This article has been cited as an argument
against the use of the WHO/ISUP system. However,
given that WHO grade 1 cancers were simply
renamed as PUNLMP in that study, it should not
even be considered as having used the WHO/ISUP
system.
Before discussing the prognosis of tumors using the
WHO/ISUP system, it is worthwhile to briefly highlight differences among studies in terms of their
inclusion criteria and definition of progression.
Some reports restrict their study to only cases without invasion (pTa). Although stage pT1 disease is
still considered to be “superficial bladder cancer,”
once lamina propria invasion is identified, these
patients are at an increased risk of subsequently
developing detrusor muscle (muscularis propria)
invasion (stage pT2). Consequently, including pTa
(noninvasive) and pT1 (superficially invasive)
tumors leads to a heterogeneous group of patients.
Another difference in inclusion criteria is that some
studies include patients with CIS, while others do
not. CIS is one of the more aggressive lesions in the
bladder despite its flat morphology. Including
patients with CIS in a study of noninvasive or minimally invasive papillary carcinomas adds an additional variable, which must be taken into account
when analyzing prognosis. The definition of progression also varies among studies. Some include
progression from pTa to pT1, while others require
evolution to pT2. In some but not other studies, a
change in grade or the development of CIS is considered progression.
Figure 8D. Papillary Carcinoma, High Grade
areas of higher grade tumor. Studies are needed to
determine how significant a minor component must
be in order to have an impact on prognosis.
d) Papillary Urothelial Neoplasms: Prognosis
One of the earliest papers reported to have used the
WHO/ISUP system has led to misconceptions regarding the classification system. In October 1998, a
manuscript was submitted for publication and eventually published in Cancer entitled “Papillary
Urothelial Neoplasms of Low Malignant Potential”
(Level 3, [124]). This article was submitted before
the WHO/ISUP classification system was even published and before there were detailed illustrations or
descriptions on how to classify tumors using the new
system. The authors took lesions that were formerly
called WHO grade 1 and designated them as
PUNLMP. As described above, there is not a one-toone translation between the WHO/ISUP and WHO
1973 classification systems. If these lesions were
analyzed correctly using the WHO/ISUP classification system, many of these lesions would not be classified as PUNLMP, but would be diagnosed as low
grade urothelial carcinomas. It is no surprise that the
cases they classified as PUNLMP had an increased
The first article to use the WHO/ISUP system as it
was meant to be used and to correlate its lesions with
prognosis was published by Desai et al. in 2000
(Level 2, [125]). The authors examined 120 pTa and
pT1 tumors, including patients even if they had CIS.
They showed significant differences in prognosis
among the various categories. While papillomas did
not recur or progress, and PUNLMP tumors recurred
but did not progress, low grade and, to a greater
extent, high grade carcinomas experienced progression and, in some cases, death (Table 3).
In 2001, Alsheikh et al. examined 49 patients with
pTa tumors who did not receive any additional treatment after an initial transurethral resection (Level 2,
[126]). The authors focused on the differences between the 20 PUNLMPs and 29 low grade carcinomas. Twenty-five percent of the PUNLMPs recurred,
in contrast to 48% of the low grade carcinomas. Of
the 2 patients who progressed to high grade muscle-
30
Table 3. Relation of WHO/ISUP Grades to Progression [125]
Papilloma
(n=8)
PUNLMP
(n=8)
Low Grade
(n=42)
High Grade
(n=62)
Recurrence
0%
33.3%
64.1%
56.4%
Any Stage Progression
0%
0%
10.5%
27.1%
Lamina Propria Invasion
0%
0%
2.6%
8.3%
Detrusor Muscle Invasion
0%
0%
5.3%
6.3%
Metastases/Death
0%
0%
10.6%
25.0%
carcinomas using the WHO/ISUP classification system. Since most WHO grade 3 cases are aggressive
tumors and already have coexisting invasive cancer,
very few patients with WHO grade 3 tumors initially satisfied the criteria of having noninvasive papillary carcinoma; of the 363 noninvasive papillary carcinomas, only 3.6% were classified as WHO grade 3.
Furthermore, some of the WHO grade 3 noninvasive
papillary cancers had coexistent CIS. With the
WHO/ISUP system, Holmang et al. classified 28%
of the cases as high grade carcinoma, with an increased risk of progression.
invasive carcinoma, both were initially low grade
carcinomas. There was also one patient who progressed to CIS who also initially had low grade carcinoma.
The largest study to date looking at the WHO/ISUP
classification system is that by Holmang et al. (Level
2, [127]). Of the 363 pTa tumors evaluated, 83% of
the patients received no additional treatment until
later. Progression was defined as tumors that developed lamina propria invasion beyond the muscularis
mucosa or metastatic disease. Most patients with
PUNLMP had no evidence of disease, and only a
small percentage of patients had tumor at last followup, but no one was dying of disease. In contrast,
patients with low grade carcinoma had an increased
risk of tumor being present at last follow-up, in addition to a small percentage of patients dying of disease. Patients with high grade carcinoma had a larger
risk (16%) of dying of disease (Table 4). Low and
high grade carcinomas had similar risks of recurrence, in contrast to a lower risk with PUNLMPs. In
terms of progression, PUNLMPs and low grade carcinomas had similar risks compared to an increased
risk with high grade carcinomas. When the authors
compared the risk of progression between WHO
grade 2 and grade 3 lesions, there was a greater difference in terms of the risk of progression compared
to the difference between low grade and high grade
Pich et al. also focused their investigations on differences between PUNLMPs and low grade carcinomas (Level 2, [128]). In addition to recurrence and
progression, p53 expression and proliferation markers were analyzed. Sixty-two pTa tumors were
studied. No patients received adjuvant therapy until
recurrence. Progression was defined as any invasion
or metastases. Differences in recurrence were noted
between PUNLMPs and low grade cancers with
recurrence rates of 47.4% and 76.7%, respectively.
While none of the PUNLMPs progressed, 11.6% of
the low grade carcinomas progressed. There was also
a difference in the recurrence-free interval between
PUNLMPs and low grade carcinomas, with 76- and
15-month recurrence-free intervals, respectively.
Differences were also noted between the 2
Table 4. Relation of WHO/ISUP Grades to Progression [127]
PUNLMP
(n=95)
Low Grade
(n=160)
High Grade
(n=108)
No Evidence of Disease
94%
76%
67%
Alive With Disease
3%
10%
9%
Dead With Disease
1%
6%
7%
Dead of Disease
0%
4%
16%
No Follow-up
2%
4%
1%
31
WHO/ISUP grades in their p53 expression, mitoses,
and MIB1 (a proliferation marker) activity.
vide clinicians with this essential information in an
unambiguous manner.
Cina et al. have also analyzed tumors using the
WHO/ISUP classification system for p53 expression
and proliferation as measured by KI67 (Level 3,
[129]). Increases in p53 expression of 0.4%, 2.9%,
and 25.7% were documented in cases of PUNLMP,
low grade carcinoma, and high grade carcinoma, respectively. Proliferation also increased among the 3
grades: 2.5%, 7.3%, and 15.7%, respectively. In a
separate study, 134 patients with pTa tumors without
prior or concurrent CIS or invasion were analyzed
(Level 2, [130]). Progression was defined as tumor
recurrence with any invasion (pT1 or pT2) or CIS.
The 90-month actuarial risks of progression for
WHO papilloma and carcinomas grade 1, grade 2,
and grade 3 were 0%, 11%, 24%, and 60%, respectively. The corresponding progression rates for
WHO/ISUP papilloma, PUNLMP, low grade and
high grade carcinomas were 0%, 8%, 13%, and 51%,
respectively. WHO grade (P = 0.003) and tumor size
(P = 0.03) and WHO/ISUP (P = 0.002) and tumor
size (P = 0.04) independently predicted progression.
Although WHO grade 3 cancers had a more rapid
progression rate and a slightly worse long-term progression rate compared to WHO/ISUP high grade
cancer, only 4.5% of tumors were WHO grade 3 as
compared to 21.6% classified as WHO/ISUP high
grade. These findings are similar to Holmang’s
study, where only 3.6% of tumors were classified as
WHO (1973) grade 3, as compared to 28% classified
as WHO/ISUP high grade carcinoma (Level 2,
[127]). As patients with high grade noninvasive papillary carcinoma are not treated with definitive therapy (such as cystectomy), the goal should not be to
restrict this high risk group to a very small population, but to expand it to include all patients at significant risk of progression for close monitoring.
Invasion of the lamina propria is characterized by
nests, clusters, or single urothelial cells, which have
breached the epithelial basement membrane. A useful feature in identifying invasion is the presence of
marked retraction artifact around the infiltrating cellular clusters, which may closely mimic lymphovascular invasion. Since vascular invasion is uncommon
in urothelial carcinomas limited to the lamina propria, care should be taken not to overinterpret this
artifact. As invasion extends into the mid-level of the
lamina propria, carcinoma will eventually infiltrate
into wispy smooth muscle bundles, the muscularis
mucosae. Although several studies have shown that
the depth of lamina propria invasion with respect to
the muscularis mucosae has prognostic significance,
the consensus committee chose to make substaging
of lamina propria invasion optional. Pathologists are
encouraged, however, to assess the extent of invasion (focal vs. extensive) to help guide urologists to
an appropriate treatment plan.
The distinction between invasion of the muscularis
mucosae and muscularis propria (detrusor muscle) is
critical but may be difficult. The presence of nu-merous blood vessels admixed with small bundles of
smooth muscles favors muscularis mucosae whereas
dense bundles of smooth muscle characterize the
muscularis propria (detrusor muscle). It is recognized that the depth of invasion will not be able to be
accurately determined in all instances. In these
equivocal biopsies, the pathologist should convey
his/her uncertainty to the urologist, which will likely
initiate a restaging procedure.
Three final comments on depth of invasion are warranted. First, the pathologist has done his job if he
can discriminate between invasion of the muscularis
mucosae and muscularis propria on a bladder biopsy
specimen. Attempts at substaging the depth of invasion of the muscularis propria on a biopsy specimen
are neither required nor expected. Definitive assessment of the depth of invasion should be reserved for
the final resection specimen. Second, the presence of
adipose tissue admixed with tumor on a biopsy
specimen is not necessarily indicative of extravesical
spread of tumor. In fact, fat may be present at any
level of the bladder including both the lamina propria
and muscularis propria. Lastly, the consensus committee recommends mentioning the presence or
absence of muscularis propria in all bladder biopsy
specimens as this provides useful feedback to the
urologist regarding biopsy technique and adequacy.
e) Invasive Urothelial Carcinoma
Confusion in terminology is not limited to the diagnostic entities in the various classification schemes,
as it also exists for the descriptive terminology
applied to invasive urothelial lesions. Various terms
include “superficial muscle invasion,” “deep muscle
invasion,” “muscle invasion (not otherwise specified),” and “superficial bladder cancer.” The latter
term is particularly confusing as it could be applied
to CIS, noninvasive papillary neoplasms, or truly
invasive urothelial carcinoma. Due to variations in
treatment and prognostic significance related to the
depth of invasion of bladder tumors, the consensus
group developed several recommendations to pro-
32
Summary
of cases after 3 separate evaluations [133]. In another study, 35% of tumors initially diagnosed as stage
pT1 were downstaged to pTa, and 3% were upstaged
as pT2 to pT4 tumors [134]. In a recent study, there
was complete interobserver agreement on pT1 stage
among reviewers in 80% of cases, which rose to 88%
after a second review [135]. In this study, of the 63
tumors originally diagnosed as stage pT1, the consensus diagnosis by experienced genitourinary
pathologists resulted in downstaging of 35 (56%) to
pTa and upstaging of 8 (13%) to pT2 to pT3 tumors
[135]. Progression was more common in the 20 consensus-confirmed stage pT1 cases (25%) when compared to the 55 original pT1 cases (20%) [135].
Tumors that were downstaged to pTa showed less
frequent progression than the stage pT1 tumors (17%
vs. 25%) confirmed when reviewed. It was concluded that prognostic variation resulting from observer
variability in staging and grading is considerable
with significant implications for patient management
[135].
The potential advantages of the WHO/ISUP system are: 1) acceptance across a broad spectrum of
uro-logical pathologists allowing for uniform terminology and common definitions; 2) detailed
definitions of various preneoplastic conditions and
various grades of tumor, hopefully leading to
greater interobserver reproducibility; 3) more or
less consistent terminology used in the
WHO/ISUP system and urine cytology, creating a
consensus classification between cytology and
histopathology; 4) creation of category of tumor
that identifies a tumor (PUNLMP) with a negligible risk of progression, whereby patients avoid the
label of having cancer with its psychosocial and
financial (i.e., insurance) implications. These
patients are also not diagnosed as having a benign
lesion (papilloma), whereby they might not be followed as closely. Whether this classification system also helps to stratify patients for further treatment remains to be studied; 5) identification of a
larger group of patients at high risk for progression
for urologists to more closely follow; and 6) recommendations for reporting extent of invasive carcinoma in an unambiguous manner, essential for
proper treatment and management.
The prognosis of patients with pT1 tumors is highly
variable. There is a need for an accurate, easy-to-use,
reproducible substaging system to stratify patients
into different prognostic groups. Several studies
have explored the utility of muscularis mucosae for
subclassification of pT1 tumor [136-142]. Muscularis mucosa consists of thin and wavy fascicles of
smooth muscle, which are frequently associated with
large caliber blood vessels. Muscularis mucosa can
be identified in only 15% to 83% of biopsy specimens, and 6% of radical specimens do not have muscularis mucosa [143-145]. Thus, the “large” vessels
have been used as a surrogate marker of muscularis
mucosa in all published studies that have proposed
T1 substaging based on muscularis mucosa invasion.
For example, Angulo et al. were able to identify muscularis mucosa in 39% of their cases and utilized the
blood vessel landmark in a remaining 26% [139].
Thus, in 35% of their cases, substaging could not be
performed. Platz et al. identified muscularis mucosa
in only 33% of their cases [140]. Furthermore, when
they used the vascular surrogate anatomic landmark
in the remainder of the cases, they did not find any
prognostic significance in substaging pT1 disease
[140]. These practical problems have prompted
recent questioning as to whether substaging pT1 disease based on the muscularis mucosa is the best system, and, as a consequence, substaging of pT1
tumors based on muscularis mucosa invasion is not
universally advocated [105].
In 2004, the WHO made its recommendations on
the classification of noninvasive urothelial lesions
(Level 4, [131]). The recommendations are essentially the same as the 1998 WHO/ISUP system,
and thus there is now only 1 unified nomenclature
system.
2. STAGING OF BLADDER CANCER
Pathologic stage is one of the most important
prognostic factors in bladder cancer. Accurate staging is critical for patient management. The 2002
TNM (tumor, lymph nodes, and metastasis) staging
system defines pT1 tumors as those invading the
lamina propria, but not the muscularis propria; pT2
tumors as those invading into the muscularis propria;
pT3 tumors as those invading perivesical tissue; and
pT4 tumors as those invading into other organ structures (prostate, uterus, vagina, pelvic wall, or abdominal wall).
a) pT1 Tumor
The diagnosis of pT1 tumor is often difficult, with
substantial interobserver and intraobserver variability [132]. In one study, 7 experienced pathologists
could agree on lamina propria invasion in only 61%
In 1999, Cheng et al. proposed a novel system of
33
d) pT4 Tumor
substaging pT1 tumors based on the micrometric
measurement of the depth of invasion of tumor into
the subepithelial connective tissue [143,145]. They
studied a series of 55 patients with stage pT1 urothelial carcinomas diagnosed on TURBT specimens and
eventually treated by cystectomy [143]. By using an
ocular micrometer to measure the depth of invasion
from the mucosal basement membrane, they found a
significant correlation between depth of invasion in
the TURBT specimen and final pathologic stage at
cystectomy. A 1.5 mm of depth of invasion predicted
advanced stage of disease at cystectomy with a sensitivity of 81%, a specificity of 83%, and positive
and negative predictive values of 95% and 56%, respectively [143]. They further applied the same criteria to a group of 83 consecutive patients diagnosed
with pT1 bladder cancer and found a 5-year progression free survival of 67% in patients with a depth of
tumor invasion greater than 1.5 mm, compared to
93% for those tumors with a depth of invasion less
than 1.5 mm [145].
The classification of bladder carcinoma involving
the prostate as pT4 tumors has been debated. Esrig et
al. studied 143 bladder cancers with prostatic
involvement and divided them into 2 groups; group I
were those tumors that have penetrated the full thickness of the bladder wall to involve the prostate and
group II were those tumors that involved the prostate
through the prostatic urethra [149]. Five-year overall survivals were 21% and 55% for group I and
group II patients, respectively. Among group II
patients, the presence of stromal invasion was associated with worse prognosis compared to those
involving urethral mucosa only [149]. Similarly,
Pagano et al. found that 5-year survival was only 7%
among group I patients, compared to 46% among
group II patients [150]. In group II patients, all
patients with urethral mucosal involvement were
alive and free of disease, compared to a 40% to 50%
survival among patients with stromal invasion.
b) pT2 Tumor
III. DIAGNOSIS
The clinical utility of substaging of pT2 tumors has
been questioned [146]. The 2002 TNM staging system subclassifies pT2 tumor into 2 categories: cancer
invading less than one-half of the depth of muscular
propria (pT2a) and cancer invading greater than onehalf of the depth of muscularis propria. A number of
studies have compared clinical outcomes between
pT2a and pT2b tumors and have failed to find a
prognostic difference between these 2 groups.
Among 145 bladder cancer patients, 5-year survival
was 65% for patients with pT2a tumor, compared to
61% for patients with pT2b tumors [147]. Pollack et
al. studied 49 patients and found no difference in 5year survival between patients with pT2a tumor
(78%) and pT2b tumors (77%). In a multivariate
analysis, Cheng et al. found that tumor size, rather
than the depth of invasion, was predictive of distant
metastasis-free and cancer-specific survival in
patients with muscularis propria invasion [146].
1. BLADDER CANCER SCREENING
The goal of screening is to improve survival by
detecting bladder cancer at an earlier stage. The optimal method to determine whether screening accomplishes this goal is a prospective randomized controlled trial that compares the mortality of screened
and unscreened patients. Unfortunately, such a trial
has not been completed. Nonetheless, a review of the
literature may provide insight into bladder cancer
screening.
a) Background
In 1968, the World Health Organization outlined
principles for early disease detection (Level 4, [151]):
1. The condition sought should be an important
health problem.
2. There should be a suitable test or examination
which is valid, reliable, inexpensive, easy and
quick to perform, and acceptable to the population
undergoing testing. The efficacy of the test must
be satisfactory as determined by sensitivity, specificity, and positive predictive value.
3. The natural history of the condition should be adequately understood.
In 1977, a state-of-the-art conference on bladder cancer screening addressed these principles and concluded (Level 4, [152]):
c) pT3 Tumor
The subdivision of pT3 tumors into pT3a (tumors
with microscopic extravesical tumor extension) and
pT3b (tumors with gross extravesical extension) is
also controversial. Quek et al. examined 236 patients
with pT3 tumor [148]. With a median follow-up of
8.9 years, no recurrence or survival difference was
found between patients with pT3a and pT3b tumors.
Lymph node and surgical margin status were the
only factors associated with patient prognosis.
34
1. Bladder cancer is suitable for screening because it
is a disease with serious consequences.
c) What Tests Should Be Used for Screening?
The ideal screening test is noninvasive, inexpensive,
and exhibits high sensitivity, specificity, and accuracy. Tests that may be utilized for bladder cancer
screening include hematuria testing, cystoscopy,
bladder imaging, urine cytology, and bladder tumor
markers (nuclear matrix protein, telomerase,
hyaluronic acid, etc.). Bladder imaging with intravenous urogram or ultrasound often fails to detect
bladder tumors (Level 3, [160]). Cystoscopy and
bladder wash cytology are too invasive for routine
use. While no tests have been adequately evaluated
for bladder cancer screening, voided urine cytology
and chemical dipstick for hematuria are the only tests
in which screening trials have been conducted with a
large sample size or with long-term follow-up.
1. DIPSTICK FOR HEMATURIA
The rationale for utilizing hematuria as a screening
test is that nearly 85% of patients with bladder cancer have painless hematuria (microscopic or gross).
Although screening should be performed in high risk
patients, most screening studies have evaluated
hematuria testing in the general population (asymptomatic patients).
• Studies examining a single screening test: In a
retrospective study of 20 571 asymptomatic patients
undergoing a single chemical dipstick test for hematuria (men > 35 and women > 55), the urologic cancer rate was the same in patients with and without
microscopic hematuria (Level 3, [161]). The authors
concluded that these findings are consistent with the
“lack of recommendation for screening for microhematuria among asymptomatic adults.” This conclusion was based on screening with a single hematuria
test. However, hematuria from bladder cancer may
be intermittent and its detection may require repetitive screening (Level 3, [162,163]). Studies that utilize repetitive screening may be more applicable to
clinical practice.
• Studies examining repetitive screening: A total of
2356 asymptomatic men aged 60 years and above
underwent repetitive screening for hematuria with a
chemical strip (Level 3, [164-166]). Bladder cancer
was found in 17 men. At the time of initial diagnosis,
none of the patients had muscle-invasive cancer, but
9 patients had tumors with a high risk of progression
(CIS or stage T1). After 7 years of follow-up, 2 of 9
patients (22%) progressed to muscle-invasive disease and 3 of 9 (33%) died from bladder cancer.
Thus, the screening test detected life-threatening
cancer and detected these cancers at an early stage
2. Urine cytology has the characteristics of a good
screening test (for high grade cancers only), including high sensitivity, high specificity, low cost,
and little inconvenience. Cytology has a high positive predictive value when used in populations
with a high prevalence of bladder cancer.
3. Data on the natural history of bladder cancer (with
regard to screening) were lacking.
This state-of-the-art conference reconvened in 1989
(Level 4, [152]). Although the natural history of bladder cancer was better understood, definitive screening recommendations were hindered by the lack of
clinical trials. Subsequently, computer models suggested that screening may be cost-effective and may
reduce mortality from bladder cancer (Level 3,
[153,154]). However, there still is insufficient clinical data to confirm these models.
Although the current data is inconclusive, it serves as
a foundation for developing screening protocols.
When designing a screening program, two crucial
questions must be considered: “Who should be
screened?” and “What tests should be used for
screening?”
b) Who Should Be Screened?
The performance of a screening test improves as the
prevalence of the disease increases. In the general
population, the low prevalence of bladder cancer
limits the utility of screening. However, patients at
high risk for bladder cancer have a high prevalence
of the disease, leading to a more favorable performance by a screening test. Thus, screening should
probably be confined to patients at higher risk for
bladder cancer.
Screening studies have been conducted in high-risk
populations exposed to occupational carcinogens
including beta-naphthylamine (Level 4, [155-157]),
4,4’-methylene-bis-2-chloroaniline, (Level 4, [155];
Level 3, [158]), benzidine [155], and coal-tar-pitch
volatiles [159]. The screening protocols usually
included medical history (including voiding symptoms and other risk factors for bladder cancer),
hematuria testing, and voided urine cytology.
Although these studies may help serve as models for
the development of screening protocols, they have
not proven that screening improves outcome in highrisk patients.
35
Summary
when cure may have been achieved. The authors
concluded “…as their disease was identified at a
superficial stage it may have been amenable to
aggressive early management…” [166].
The optimal screening test and testing interval are
unclear. The population that would benefit most
from bladder cancer screening is unknown; however, patients at high risk for bladder cancer are
thought to be the best candidates for screening.
Screening has been conducted mainly by hematuria testing and urine cytology. The role of other
tumor markers is unclear. Screening may detect
bladder cancers at an earlier stage and may reduce
cancer-related deaths. However, there is still no
conclusive data that proves that screening reduces
mortality from bladder cancer.
Outcome from bladder cancer in 1575 asymptomatic
men aged 50 years and above undergoing repetitive
hematuria screening with a chemical strip (screened
cases) was compared to men with newly diagnosed
bladder cancer from the Wisconsin cancer registry in
1988 (unscreened cases) (Level 3, [167]). At the time
of diagnosis, screen-detected cancers were less likely to be muscle-invasive than unscreened cancers
(4.8% vs. 23.9%, respectively). In cases of grade 3
cancer, 0% of the screen-detected tumors were muscle-invasive, whereas 51.9% of unscreened tumors
were. Furthermore, death from bladder cancer (within 2 years of diagnosis) was significantly less in the
screened group compared to the unscreened group
(0% vs. 16.4%, respectively). The authors concluded
that “hematuria...screening detects high grade cancers before they become muscle invading and significantly reduces bladder cancer mortality.” These
studies suggest that hematuria screening in the
general population may help detect bladder cancer
at an earlier stage and may reduce cancer -related
deaths.
2. SIGNS AND SYMPTOMS
The most common presenting symptom of bladder
cancer is painless hematuria, which occurs in about
85% of patients. In reality, nearly all patients with
cystoscopically detectable bladder cancer have at
least microhematuria if enough urine samples are
tested [168].
a) Gross Hematuria
The vast majority of bladder cancers are diagnosed
as a result of evaluating patients for hematuria. Total
gross hematuria (blood in the urine throughout micturition) without pain is the typical sign suspicious
for bladder cancer. Kretschmer studied 860 patients
with hematuria and found that 28% of the patients
had bladder cancer [169]. Varkarakis et al. studied 95
patients with gross painless hematuria and found 12
patients (13%) with bladder cancers [170]. In a similar study of 1000 patients with gross painless hematuria by Lee et al., 15% of the patients had bladder
cancers [171]. Careful characterization of hematuria
as initial, terminal, and total hematuria is important
to identify the location of bleeding. Therefore, with
these high incidences of bladder cancer in patients
with gross hematuria, the modern examination by
flexible cystoscopy seems to be necessary. However,
hematuria is quite often intermittent so that a negative result on 1 or 2 specimens has little meaning in
ruling out the presence of bladder cancer.
2. URINE CYTOLOGY
The state-of-the-art conference on bladder cancer
screening in 1977 determined that urine cytology has
the characteristics of a good screening test (for high
grade cancers only) because of its high sensitivity,
high specificity, low cost, and minimal inconvenience (Level 4, [152]). Unfortunately, studies evaluating urine cytology as a screening test are sparse.
One study utilized an annual voided urine cytology
to screen aluminum production workers exposed to
coal-tar-pitch volatiles (Level 3, [159]). Cancers
detected during screening were more likely to be
noninvasive than cancers detected before screening
was initiated (63% vs. 39%, respectively). Survival
was improved in patients whose cancer was detected
by screening; however, the improvement had not
achieved statistical significance at the time of the
report.
b) Microscopic Hematuria
d) Screening Interval
Mohr et al. reported that asymptomatic microhematuria occured in 13% of the general population and of
those patients only 0.4% had urothelial neoplasia
[172]. On the other hand, Golin et al. found that 16
patients (6.5%) had bladder cancer among 246
patients with asymptomatic microscopic hematuria
who were referred to a urology clinic [173]. Mohr
Current evidence suggests that screening should
probably be performed annually (Level 3,
[159,163]).
36
3. URINARY CYTOPATHOLOGY
also showed the poor correlation between the number of red blood cells per high power field and the
probability of significant disease [172].
a) Definitions
1. BLADDER CANCER
The policy regarding microscopic hematuria is still
unclear, except in patients over 50 years of age, who
should be examined in the same way as for macroscopic hematuria, since the incidence of underlying
malignancy in patients over 50 years with asymptomatic hematuria is 5%, while an incidence of
10.5% is found with symptomatic microscopic
hematuria [174].
Bladder cancer is an ill-defined term ordinarily used
to connote malignant neoplasms occurring in the urinary bladder. Most of these neoplasms are urothelial
(transitional cell) but bladder cancers can be squamous, glandular, small cell, and even non-epithelial.
If the term is confined to urothelial neoplasms, it
actually refers to a group of tumors that range from
phenotypically and biologically benign to phenotypically and biologically malignant. Anyone attempting to understand the role of any detection method
must be aware that the term “bladder cancer” does
not define a homogeneous group of neoplasms with
aggressive behavior but includes neoplasms that are
histologically and biologically benign.
Moreover, screening with dipstick for asymptomatic
hematuria is not recommended by the American
Cancer Society or the Canadian Taskforce [175].
Mayo Clinic investigators reviewed the charts of
2312 patients with asymptomatic microscopic hematuria [176]. The positive predictive value for bladder
cancer was too low (0.5%) to warrant mass screening, as reported by Mohr et al. [172].
2. UROTHELIAL NEOPLASM
A urothelial neoplasm is a misregulated proliferation
of urothelial cells differentiating toward urothelium.
Nearly all such neoplasms occur in organs lined by
urothelium and most of these arise in the urinary
bladder. When processed and viewed using a light
microscope, urothelial neoplasms comprise a morphologic spectrum from normal epithelium on a delicate fibrovascular stalk to anaplastic cancers with or
without homologous or heterologous elements. As
defined and illustrated in the 1998 WHO/ISUP Consensus classification, these neoplasms have been
named as follows [105]:
Therefore, routine screening for microscopic hematuria may be indicated only for high-risk populations
such as those exposed to bladder carcinogens and/or
heavy smokers.
c) Other Symptoms
The symptom complex of bladder irritability and urinary frequency, urgency, and dysuria is the second
most common presentation of bladder cancer, and is
usually associated with diffuse CIS or invasive bladder cancer.
Hematuria associated with irritative symptoms such
as frequency, dysuria, and urgency should be carefully examined after infection and neurogenic bladder have been ruled out since it may indicate relatively advanced tumors or CIS that extends to the
bladder neck or the prostatic urethra. Jewett suggested that urinary frequency was an important symptom
that was complained of in about one-third of the
cases [177].
• papilloma;
• papillary urothelial neoplasm of low malignant
potential (PUNLMP);
• urothelial carcinoma, low grade;
• urothelial carcinoma, high grade (+/- variants);
and
• carcinoma in situ (CIS).
CIS of the bladder may be asymptomatic or may produce severe symptoms of urinary frequency, urgency, and dysuria [178].
The nature of urothelial dysplasia remains in dispute. Some experts include it among the neoplasms,
whereas others consider it a precursor, and still others think of it as a reactive process with the potential
to transform. In the WHO/ISUP scheme, dysplasia is
defined as a flat urothelial lesion that “falls short” of
CIS.
Other symptoms and signs of bladder cancer include
flank pain due to ureteral obstruction, lower extremity edema, and a palpable pelvic mass. Very rarely,
patients present with symptoms of advanced disease,
such as weight loss and abdominal or bone pain from
distant metastases.
The 1998 WHO/ISUP scheme is not simply a renaming of the categories G1, G2, and G3 of the 1973
system. The major gain is the removal of the term
“carcinoma” from the lowest grade tumors (essen-
However, these symptoms almost never occur without microscopic or macroscopic hematuria.
37
tially all G1). The classification recognizes the difference between the potential of the patient to develop a malignant neoplasm and the presence of such a
tumor. Other advantages include:
In fact, medical consultations from the limited information available on glass slides processed for light
microscopy require a good deal of induction and
some intuition. In addition to knowledge of the cellular features (which essentially represent descriptions of the interpretations of individuals with a special interest in the subject), other components enter
into an interpretation. These include the
• recognition that most true carcinomas are high
grade (many G2 and all G3) and that further subclassification of this group has no practical meaning,
• limitation of the intermediate group (G2) by a
more explicit histologic definition,
• adequacy of the specimen,
• recognition that CIS should not be graded, and
• confidence of the cytopathologist,
• recognition that urinary cytopathology is an
important aspect of evaluation.
• perceived consequences to the patient of a positive interpretation,
The 1998 WHO/ISUP scheme has been adopted by
the 2004 WHO committee and the 4th Series AFIP
Fascicle and is becoming widely accepted among
practicing pathologists [131,179].
• perceived consequences to the pathologist of a
misinterpretation,
• accuracy of the clinical information,
• reason for the request (screening normal, or
screening symptomatic, monitoring), and
It is important to note that whereas urothelial neoplasms seem to comprise a morphologic spectrum of
increasing degrees of anaplasia, this spectrum does
not translate into a biologic spectrum of concomitant
degrees of aggressive behavior. Urothelial papillomas and PUNLMPs, for example, lack the ability to
invade or metastasize [119,180-182]. Patients presenting with these tumors are at increased risk for an
adverse outcome but the neoplasms themselves do
not progress. Thus, any adverse outcome requires
the development of a new, high grade carcinoma.
Similarly, patients who present with urothelial CIS
(defined as a flat, noninvasive neoplasm of high
cytologic grade) develop invasive lesions during
clinical observation in less than one-third of cases,
even though the cells comprising CIS have nearly
every component of malignancy identified to date
[183,184].
• terminology used for reporting the interpretation.
As with any judgment made by a human, temporary
distractions and lack of education may play a role in
any particular case, but there is very little evidence
that these factors are important in the general application of urinary cytopathology to patient care.
b) Application of Urinary Cytopathology to Clinical
Practice
Among the many applications of urinary cytopathology (UC) to patient care, the most important is for
the detection of bladder neoplasms. Using UC,
cytopathologists can detect squamous, glandular,
small cell, and even sarcomatous lesions, but the
method is primarily used to detect urothelial neoplasms. UC is not particularly suited to screening.
The yield for primary urothelial tumors reflects the
low incidence of these lesions in the population.
Even among symptomatic individuals, the most thoroughly conducted study found only 106 cases among
35 000 “tested” (0.3%) [185].
1. URINARY CYTOPATHOLOGY
Urinary cytopathology (aka cytology) is a medical
consultation based upon a cytopathologist’s interpretation of changes in disaggregated cells as they
appear in specimens processed for light microscopy.
The literature often seems to promote the misconception that this consultation is merely an observation and that cytopathologists are “observers” (see
section on Interobserver Variation). Cytopathologists
are often asked to “read” slides, as if the information
therein required fluency in a language foreign to the
requestor and one merely needed to have acquired
fluency in it to comply. This conceit of the language
is known to the sophisticated, but it tends to create an
erroneous concept, nonetheless.
UC is most efficacious for monitoring patients for
the appearance of high grade neoplasms (including
CIS) [186]. It is especially useful for patients treated with topical agents, where the effects of therapy
tend to confound cystoscopic examination, and for
recognizing the presence of persistent or recurrent
carcinomas that may be confined to the prostatic
ducts, urethra, or distal ureters. UC interpretations
can assist the urologist in timing a cystoscopy during
patient monitoring. Patients being followed after the
diagnosis of a PUNLMP or noninvasive low grade
38
carcinoma who have no recognizable tumor cells in
their urinary specimens can undergo cystoscopy at
longer intervals than patients with tumor cells in
their UC [187]. Urinary cytopathology interpretations can be of prognostic value. Patients treated
with topical therapy who have high grade cells in
their urinary samples are very likely to come to cystectomy [188]. A negative interpretation can be reassuring in many circumstances and should not be discounted.
lesion was low grade (PUNLMP, low grade carcinoma, [G1, many G2 in 1973 WHO]). UC has the
further advantage that it is the neoplastic cells themselves that are being identified.
c) Terminology
Communication of the interpretation of a urinary
specimen is an important aspect of the consultation.
As with histologic lesions, each practice setting may
recognize the patient care implications of their particular vocabulary. Uncritical data collection from
the charts of multiple institutions for collaborative
reports may be misleading. The term “atypia,” for
example, has been rejected by many groups but considered an important indicator of risk by a few [191].
When modified by the word “severe,” many would
consider it a synonym for CIS. “Positive” and “transitional cell carcinoma” may indicate either high or
low grade tumors, the latter being associated with a
far higher false positive rate than the former. “Suspicious” calls for the question, “Suspicious for what?”
Some authors have included suspicious among the
positives for assessing results whereas other authors
have included suspicious among the negatives for the
same purpose. In at least one study, the diagnostic
yield has been configured both ways [192].
UC is less useful for the detection of low grade neoplasms. There are several reasons. The cells of low
grade urothelial tumors lack many features associated with malignancy, such as nuclear pleomorphism,
coarsely clumped chromatin, and large nucleoli. In
contrast to high grade neoplasms, the expression of
phenotypic features considered important in the
recognition of low grade neoplastic cells tends not to
occur in every cell. In tissue specimens, low grade
urothelial neoplasms are recognized as neoplastic
primarily because their cells are arranged on delicate fibrovascular stalks. Similar cells in flat urothelium cannot be recognized as neoplastic in histologic sections and are often termed “dysplasia.” In other
words, it is not the cells but the stalk that allows the
histopathologist to diagnose low grade urothelial
neoplasms.
Since the features used to classify urothelial neoplasms histologically may not be present in the cytologic sample (to wit, the stalk), Murphy has recommended the following terminology to communicate
the cytopathologic interpretation:
Other factors affect the interpretation of any individual specimen. One of the most important and least
discussed of these factors is the adequacy of sampling. In a study from the University of Florida, for
example, 23% of bladder washings from patients
having histologically documented high grade urothelial carcinomas at the time of the washing lacked
tumor cells [189]. A “negative” cytopathologic interpretation in such a situation can hardly be construed
as a diagnostic error or a failure of the method itself.
Properly performed, a bladder washing should
include the residual urine collected when the instrument is introduced plus a vigorous lavage done
immediately after a full cystoscopy is performed but
prior to any other manipulation. If the residual urine
is discarded or the operator performs an initial cystoscopy prior to the washing, diagnostic elements
can easily be lost [190].
• positive, consistent with high grade neoplasm;
• positive, consistent with low grade neoplasm;
• suspicious for high grade neoplasm;
• dysplastic cells, rule out low grade neoplasm;
• negative, neoplastic cells not identified; and
• unsatisfactory, insufficient cells for interpretation
[186].
In this lexicon, suspicious should be construed to
mean that the cells have features of a high grade neoplasm, but there are too few for an unequivocal interpretation. As those who have studied asymptomatic,
high-risk individuals have discovered, factors other
than a developing neoplasm can cause a few cells in
a urinary specimen to appear neoplastic [183,193].
We are also cautious with the interpretation of a few
malignant-looking cells in specimens from symptomatic, untreated individuals, because high grade
urothelial neoplasms in such cases should shed nu-
Fortunately for patients, nearly all aggressive urothelial neoplasms are of high cytologic grade, the type
that is readily detectable using UC. The primary
purpose of monitoring patients with UC is to detect
high grade neoplasms, as persistent or recurrent
lesions if the initial neoplasm was high grade
(including CIS), or as new tumors if the initial
39
merous cells into a urinary sample. Similarly, the
only difference between some reactive lesions, flat
dysplasias, and many low grade papillary neoplasms
is the stalk. Thus, dysplastic cells warrant attention
but in many cases can not be considered diagnostic.
Depending on the circumstances, cells with essentially the same phenotypic features can be interpreted using differing terminology in daily practice.
whether an immediate or a delayed histologic correlation;
• the grade of tumor being correlated;
• whether or not the correlation is cystoscopic only;
• the number of cytopathologists involved and their
interaction with each other as well as their
involvement in the data analysis;
The expectation that an interpretation will result in a
specific action is important to cytopathologic consultation. It focuses the mind on the evaluation and
reminds us that patients will be affected. In one practice setting, the cytopathologists expect that interpretations will lead to the following actions:
• the types of cases (primary neoplasms, persistent
or recurrent neoplasms);
positive, consistent with
high grade neoplasm
cystoscopy with
biopsies, even if no
lesions are identified
• the presence or absence of topical therapy;
positive, consistent with
low grade neoplasm
cystoscopy with biopsy
of lesions only
• the (nearly inevitable) biases contained within the
work.
suspicious for high grade
neoplasm
cystoscopy with
biopsy of lesions only
dysplastic cells, rule out
low grade neoplasm
cystoscopy with biopsy
of lesions only
One can select almost any figures from the literature.
This section is concerned primarily with discussing
the issues.
negative, neoplasm not
identified
no action
• the case mix (the percentage of neoplasms versus
negatives will affect the specificity and the predictive value);
• the histopathologic classification used for correlation; and
Specimen selection is important to diagnostic yield.
Random voided urines are well known to contain
fewer and more degenerated neoplastic cells than
bladder washings [190]. The cytopathologist must be
on heightened alert for an accurate interpretation of
voided urine, especially during follow-up. Knowledge that the patient is being followed for “bladder
cancer” is usually essential and the further information that the “bladder cancer” is high grade would be
even better. The problems associated with few
abnormal cells in a specimen are usually functional
here, especially when patients have been exposed to
topical agents. Topical agents are designed to reduce
the number of tumor cells in a urinary sample and the
combination of only a few cells and the degeneration
common to voided urine can be diagnostically daunting. If the purpose of the study is to find a way to
reduce patient instrumentation during follow-up,
then urinary cytopathology is at a disadvantage. Still,
voided UC has detected tumor cells under such circumstances and may even be positive when the bladder washings are not [190,192,194-197].
These recommendations are the result of a study that
indicated that for the entire group of four cytopathologists, high grade cells were essentially always associated with a neoplasm in the bladder at the time of
specimen collection and that dysplastic cells were
associated with a neoplasm in 60% of cases [189].
Other practice settings may achieve different results
and should perform their own studies. It is probably
inappropriate to assume that data from one setting
can be extrapolated to all others.
d) The Diagnostic Yield of Urinary Cytopathology
This subject is far from simple. The value of UC in
the detection of urothelial neoplasms depends upon a
variety of factors. These include
• the type of specimen upon which the interpretations are made - whether voided urine or bladder
washings;
• the design of the study from which the data are
taken - whether to test the method itself, compare
to other methods, assess the added yield of other
methods, or to assess UC diagnoses in daily clinical practice;
Bladder washings are associated with a higher yield
than voided urines, primarily because of better cell
preservation and more numerous neoplastic elements
in the sample. Patients must be instrumented but cystoscopy is not an adequate substitute for UC since
persistent and recurrent neoplasms are not always
• the definition of a cytohistologic correlation –
40
evident cystoscopically, especially after topical
therapy.
study compares a laboratory test performed on
voided urine with the cytopathologic consultation,
sometimes, but not always, on the same sample.
In the literature, the diagnostic yield of UC seems to
vary with the purpose of the study. If the study is
designed to assess the efficacy of the method, then
patient care implications are specifically excluded.
The cytopathologist (usually only one) is most often
“blinded” to all clinical circumstances. Cases are
grouped and examined in a concentrated fashion that
facilitates the reproduction of fine distinctions in a
visual analysis. Specimens are very often bladder
washings. It is assumed that they are representative
of the actual state of the bladder. Cytohistologic correlations with bladder biopsies are almost always the
measure of success but the correlation need not be
immediate. A cytohistologic correlation may be considered positive if the patient has a documented neoplasm many months after the positive cytopathologic interpretation. Since urothelial neoplasms are
unusual in the population and periodic biopsies of
otherwise normal people are not ordinarily possible,
the study is usually weighted with patients being followed for urothelial neoplasms and this factor is
ordinarily known to the cytopathologist.
When the study is designed to evaluate the method
itself, the diagnostic yield is most often good, even
when all grades are combined in the results, and are
especially favorable for the interpretation of high
grade neoplastic cells [194-203]. Sensitivities in the
range of 60% to 90%, specificities of 90% to 100%,
and positive predictive values (PPVs) of greater than
85% are often recorded. The higher numbers are
ordinarily achieved for bladder washings, but success has been claimed for voided urines. The numbers tend to decline when individual specimens are
compared to cases, voided urine is compared to bladder washings, and low grade neoplasms are compared to high grade cancers. Sensitivities for voided
urine specimens and low grade urothelial neoplasms
are usually reported in the range of 30% to 60%.
Specificities have remained greater than 85%, however.
When the study is designed to assess the diagnostic
yield in clinical settings, especially when the intent is
to compare UC with ancillary laboratory tests, the
numbers for sensitivity and specificity tend to fall
into the voided urine range [204-211]. Diagnostic
yields of less than 40% for high grade neoplasms are
not unusual. In 2 reviews of the literature, sensitivities in the range of 35% to 80% and specificities of
80% to 100% were most often cited [212,213]. The
reasons for this lower yield, especially in marker
comparison studies (when cytopathologists are “on
the line” compared to when they are “in the dark”)
have not been rigorously addressed. The lower yield
of the voided urines (compared to bladder washings)
upon which many of the comparison studies are
based has been well-documented. The cytopathologist is detecting actual neoplastic cells rather than a
byproduct of the neoplastic state, and this probably
accounts for maintenance of relatively high specificities and PPV.
If the purpose of the study is to assess the yield of
UC in a clinical setting, then relevant information is
not concealed from the cytopathologist, although
neither is it always provided. Many of the same factors - case selection weighted toward “cancer” cases,
assumption of specimen adequacy, type of
histopathologic classification used, endpoint of cytohistopathologic correlation, etc. - apply but the studies are different in important ways. In a clinical practice study, it is the immediate (usually histologic but
sometimes cystoscopic only) correlation that is
paramount. The correlation may include all grades of
urothelial neoplasms or separate results according to
grade. More than one cytopathologist is ordinarily
involved. The study is very often retrospective, the
cytopathologists not being aware that their interpretations will be used for publication. Cases have come
sporadically, among other types of specimens, requiring the cytopathologists to switch mental gears
rather than to concentrate their thoughts on reproducing the subtleties of urothelial tumor assessment.
In a clinical setting, there may be consequences to an
interpretation. Pathologists have been schooled to be
cautious, since a false positive interpretation is ordinarily more harmful to patients than a false negative
one. This no doubt accounts for the high specificity
of most results. Many studies have been multi-institutional reviews. In most of the recent literature, the
The diagnostic yield of UC tends to vary considerably among individual reports, a situation that has
led to a plea for more thorough education for practicing cytopathologists. The assumption that
cytopathologic interpretations could be made more
uniform by a more standard approach seems reasonable but probably does not adequately address the
issue (see section on Interobserver Variation). Confidence and aversion to the perceived consequences of
a misdiagnosis may play a more important role in
clinical practice than one might expect. In a study
41
invasive urothelial neoplasms to detect any high
grade tumors that might develop. Given adequate
samples, especially bladder washings from patients
monitored for “bladder cancer,” the PPV for an interpretation of high grade neoplasm in a UC is so high
that it can almost never be considered falsely positive. In contrast, the PPV for interpretations of low
grade neoplasm and “dysplastic cells, rule out low
grade neoplasm” is in the range of 60%, high enough
to warrant a cystoscopy but not selected site biopsies.
comparing the daily practice results in 3 different
settings, the diagnostic yield varied in unexpected
ways [204]. At the cancer referral center, where
every specimen could be assumed to have come from
a patient with cancer and only 11% of histologically
documented cases were very low grade (G1), the
sensitivity was only 66% (specificity 98%, PPV
88%). Similar figures for specificity and PPV were
recorded for the academic practice. At the private
practice, where most specimens could be expected to
be from patients with no bladder neoplasm and 33%
of histologically documented cases were very low
grade (G1), the sensitivity of 85% was associated
with a specificity of 74% and a PPV of only 56%.
Could it be that the perceived consequences of a positive interpretation at the cancer center and academic practice differed from those at the private practice
(for example more treatment versus additional evaluation)? Or could it be concern with the consequences of missing a cancer patient (fewer at the
cancer center and academic practice where many
cases are referrals versus increased medicolegal
exposure at the private prac-tice)?
The diagnostic yield of UC varies among practice
settings and a wide range of numbers for sensitivity,
specificity, and positive predictive value have been
recorded. In general, the method itself holds more
promise than has been realized in daily practice.
Increasing the efficacy in any particular practice setting may not be simply a matter of education but may
involve addressing risk aversion.
e) The Cellular Features of Urothelial Neoplasms
The cellular features of urothelial neoplasms have
been described and illustrated in numerous publications [186,189,198,201,203,204,211]. Since the features used for histologic distinctions may not be present in the disaggregated cells of cytologic samples
and, since it is not always possible to distinguish
glandular neoplasms from urothelial tumors, the
most accurate approach to classification in this area
would seem to be separation on the basis of degree
of cytologic anaplasia (Table 5).
The diagnostic yield can be affected by the definition
of a cytohistopathologic correlation. Is a positive
interpretation of high grade neoplasm a false positive if the patient is lost to follow-up? What if the
patient had had a high grade carcinoma histologically documented previously? Should PUNLMPs have
positive cytology interpretations and, if so, positive
for what? Isn’t “dysplastic cells” a closer correlation,
even though the 1973 WHO designates these tumors
as “carcinomas”? In a study conducted on our material, the PPV could vary as much as 15%, depending
on the definition of a correlation [189]. The histologic documentation of a neoplasm after a positive
cytopathologic interpretation has sometimes
required months and even years. If the endoscopist
can’t find the lesion, is the interpretation false? On
the other hand, tumor cells can apparently continue
to be shed from a resected tumor for several weeks,
even though the treatment will eventually prove
effective [214]. Should a positive interpretation during those weeks be considered erroneous?
High grade neoplastic cells may be numerous or
sparse, depending on the type of specimen, the
approach to collection, and the prior application of
topical therapy. The key diagnostic changes are
nuclear pleomorphism and coarsely granular, irregularly dispersed chromatin. Large nucleoli may
appear in high grade neoplastic cells but are rarely
numerous and not essential for interpretation. Occasionally, cells may be small with degenerated nuclei
lacking chromatin detail but the increased nuclearcytoplasmic ratios and peculiar nuclear shape of
these cells tend to reveal their nature. Importantly,
nearly all high grade neoplastic cells contain all of
the diagnostic features listed in Table 5.
In summary, urinary cytopathology is best applied
in follow-up of patients with urothelial neoplasms.
Given adequate sampling and at least 3 specimens,
up to 90% of recurrent high grade urothelial carcinomas can be detected in cytologic samples and the
positive predictive value is greater than 90%. Urinary cytopathology is less valuable for the detection
of low grade urothelial neoplasms but should be utilized for monitoring patients having low grade, non-
Low grade urothelial neoplasms are composed of
cells lacking many features of malignancy; they can
be construed as lesions composed of dysplastic cells
on delicate fibrovascular stalks. It is the stalk rather
than the cells that allows histologic classification of
these tumors as neoplasms. When disaggregated into
urinary samples, there is very little difference be-
42
Table 5. Features of Urothelial Neoplasms
Features of Urothelial Neoplasms: WHO/ISUP 1998
_______ Carcinoma ______
High Grade
Low Grade
PUNLMP
Papilloma
Configuration
Papillary
Nodular
+
+++
+++
±
+++
0
+++
0
Architecture
Normal
Abnormal
0
+++
+
±
++
0
+++
0
Cell Distribution
Even
Clustered
0
+++
+
±
+++
0
+++
0
Superficial Cell Layer
±
+
+++
+++
Nuclear Features
Pleomorphism
Fine chromatin
Coarse chromatin
Even chromatin
Irregular chromatin
Large nucleoli
Mitoses
+++
0
+++
±
+++
+
++
+
+++
±
++
0
±
+
±
+++
0
+++
0
0
±
+++
0
0
+++
0
0
0
WHO/ISUP = World Health Organization/International Society of Urological Pathology; PUNLMP = papillary urothelial neoplasm of low malignant potential; 0 = absent/rare; ± = may occur sporadically, + = occurs in some tumors but not constant; ++
= occurs in most tumors; +++ = characteristic feature, occurring in most or all cases.
From: Murphy WM, Urinary Pathology. Chicago; ASCP Press:15.
tween the cells on stalks and similar cells that might
occupy flat areas of urothelium. Therefore, low
grade and dysplastic cells will be described together.
even when the diagnostic approach recommended
here is utilized. Given the cytopathologic interpretations listed on the left, the histologic correlates on
the right can be expected [186].
Low grade/dysplastic cells are often numerous in
urinary specimens, perhaps because patients have
not been exposed to topical therapy. The abnormally
high number of cells is often the most important clue
to the presence of a low grade carcinoma or
PUNLMP and should be reported as “numerous
cells, a very low grade neoplasm cannot be excluded,” even if the cells themselves look relatively normal. Neoplastic cells tend to be loosely clustered.
They have markedly eccentric nuclei and increased
nuclear-cytoplasmic ratios. The nuclei are irregular,
a feature usually manifested by a single notch,
crease, or shallow depression. The nuclear chromatin
is more granular than normal but evenly dispersed.
Large nucleoli are not a feature of these cells but are
typical of the reactive or regenerative elements from
which they must sometimes be distinguished. Importantly, all of the features listed in Table 5 are usually not present in every cell.
high grade neoplasm
urothelial carcinoma,
high grade
carcinoma in situ
low grade neoplasm
urothelial carcinoma, low
grade
urothelial carcinoma,
high grade
dysplastic cells,
PUNLMP
rule out low grade
neoplasm
urothelial carcinoma,
low grade
The cells of squamous cell carcinomas, small cell
carcinomas, and some adenocarcinomas can be distinguished in urinary specimens but the subject is
beyond the scope of this monograph.
f) Limitations in the Use and Interpretation of
Urinary Specimens
The cytohistologic correlation is not always exact,
Consultations based on urinary specimens have been
43
Patients in the age group most likely to develop bladder neoplasms are also prone to prostatism, bladder
outlet obstruction, and trabeculated bladders. Urinary specimens from such individuals often contain
balls of cells that can be mistaken for neoplastic papillary aggregates. The cells in these balls lack features of a neoplasm and should not be interpreted as
emanating from a low grade papillary neoplasm.
extremely beneficial in certain clinical situations,
primarily to identify high grade neoplastic cells in
the bladders of patients being monitored for persistent or recurrent disease. The use of urinary
cytopathology has limitations in the following areas:
• screening the asymptomatic population;
• detection in the upper collecting system;
• detection of renal parenchymal carcinomas;
Urinary specimens from the ureters and renal pelves
are collected with instrumentation and are ordinarily
very cellular. The cells of the upper collecting system
tend to be larger than cells from the bladder and tend
to have higher nuclear-cytoplasmic ratios, 2 features
important to the assessment of low grade neoplasms.
The absence of other features of a low grade neoplasm (eccentric nuclei, increased chromatin, and
nuclear irregularities) facilitates the correct interpretation in most instances. Nevertheless, we recommend that a cytopathologic interpretation of low
grade neoplasm be made and accepted with caution
when specimens represent the upper collecting system.
• detection of prostatic carcinomas;
• localization of neoplasms;
• detection of nonaggressive neoplasms;
• detection of some adenocarcinomas and some
squamous cell carcinomas of the urinary bladder;
• detection of nonurothelial neoplasms;
• detection of neoplasms with little or no surface
components, even though they may be deeply
invasive;
• detection in single specimens versus multiple
specimens from the same patient; and
Urinary calculi have traditionally been listed among
the confounding factors in the interpretation of urinary specimens but this should not be the case.
Stones may cause regenerative changes in urothelial
cells but these changes should be readily distinguishable from those of a neoplasm, especially when socalled “papillary” aggregation is discounted as an
important diagnostic feature.
• detection in random voided urine, especially versus bladder washings.
The interpretation of urinary specimens can be confounded by nuclear changes caused by polyoma
viruses, most commonly BK. Polyoma viruses are
ubiquitous in the population but pathogenic to the
kidney only in patients with disorders associated
with immunosuppression. In such cases, numerous
cells with increased nuclear-cytoplasmic ratios and
irregular nuclei can appear in urinary samples. Ordinarily, these cells have the smudged nuclear chromatin typical of viral infection. The fact that many
patients have been treated with cyclophosphamide
may further confound the interpretation of any particular case.
g) Urinary Cytopathology and Ancillary Tests
A good deal of the recent interest in the early detection of “bladder cancer” centers on finding ways to
augment rather than replace urinary cytopathology.
Many of these methods are designed to recognize
substances in urine that can be measured with laboratory tests alone but some require prior identification of the abnormal (tumor?) cells themselves. Perhaps the best studied of these latter methods is image
cytometry [192,205,207,211,215]. Total DNA, expressed as DNA ploidy, can be quantified on selected cells and the results recorded in histograms. In
certain cases, this approach can add sufficient confidence to allow an interpretation of “positive” rather
than “suspicious” or “atypical.” If enough abnormal
cells are present, it may not be necessary to assess
them by standard light microscopy but to simply create a histogram from Feulgen-stained material
instead. DNA aneuploidy is primarily a feature of
high grade urothelial neoplasms, those that are most
readily recognized in urinary samples using light
microscopy alone.
Electrocautery, applied prior to specimen collection,
can alter the shape and cytoplasmic orientation of
neoplastic cells, thus destroying features important
to accurate interpretation.
Exposure of urothelium to alkylating agents such as
mitomycin C often results in enlargement and
increased chromatin in the nuclei of superficial cells.
In fact, nearly every feature described for high grade
malignancy can be seen in superficial cell nuclei.
Fortunately, superficial cells retain their very low
nuclear-cytoplasmic ratios and polygonal shape even
after exposure to alkylating agents, thus allowing
accurate assessment by knowledgeable cytopathologists.
44
Abnormal cells in urinary specimens can be assessed
for chromosomal aberrations using in situ hybridization or fluorescence in situ hybridization (FISH)
[215-217]. If a positive result is defined in terms of
only a few cells, this approach can detect recurrent
disease long before sufficient cells have accumulated
to form a lesion that can be identified by other methods. Of course, the definition of “positive” on the
basis of very few cells (1-5 in various publications
on the subject) creates its own problems. How many
cells are required to achieve the critical mass necessary for a functional recurrence?
gle nomenclature and, when disagreement on the
interpretation occurs within the same nomenclature
system, additional cytopathologist education in the
cellular features of urothelial neoplasms. The notion
that a uniform nomenclature applied by a diagnostic
clone of cytopathologists would significantly
improve patient care cannot be accepted at face value
any more than the proposition that serum PSA (uniformly assessed and reported in standard units) has
resulted in a uniform approach to diagnosis and
treatment. As long as pathologic diagnoses represent
consultations based on the interpretations of human
beings, a certain level of interobserver variation will
exist and must be accepted.
Abnormal cells in urinary specimens can be reacted
with various antibodies considered to be indicative
of neoplastic differentiation [206,207,218,219]. Utilization of these aids can increase sensitivity, oftentimes too much. Perhaps just as importantly, they can
allow the cytopathologist to make an unequivocal
interpretation in selected cases.
If interobserver variation in pathology is to be
reduced, it is important to understand the nature of
pathologic interpretations. Central to this discussion
is the fact that there is no phenotypic feature or group
of features that all neoplastic cells have all of the
time. Accurate assessment of whatever phenotypic
changes are present at any particular time requires
intuition as well as knowledge. If human carcinogenesis is the result of misregulation of an individual’s “normal” physiology, then the early detection of
a neoplasm using light microscopy requires recognition of phenotypic clues to dynamic processes and
assumes that there is a direct and timely correlation
between them.
Abnormal cells identified by the cytopathologist can
be further analyzed morphometrically [220]. Precision is facilitated by a limited number of measurements augmented by certain calculations.
Many of these approaches are not new. They have
not been widely adopted primarily because the
increased diagnostic yield does not justify the expense in time, training, and physical resources. Like
other methodologies, the benefits are mostly in the
detection of low grade, nonaggressive lesions - circumstances in which early detection is not favorably
balanced by the level of false positive and negative
results.
Pathologists cannot accurately define the mental processes through which an interpretation is reached.
The exercise has been tried by computer experts over
many years. In the end, success in instructing a computer to interpret cellular changes was achieved by
showing the instrument the image and asking it to
“remember” that image and all future similar examples (neural net).
The important need in early detection of urothelial
neoplasms is for a method to identify high grade
cancers and the research community should be
urged, if not required, to focus on this aspect of the
issue rather than being rewarded for a generalized
approach that detects nonaggressive lesions.
Pathologists do not “read” slides, as if all of the
information were clearly written in some arcane text
that only required fluency to decipher. Rather, they
function more as critics, who are given a single snapshot of a game in progress and expected to divine the
game and its likely outcome. Oftentimes, the snapshot contains the scoresheet but sometimes it contains only a single play and only a few of the players.
h) Interobserver Variation
The subject of urinary cytopathology cannot be
addressed without discussing interobserver variation.
As a medical consultation rather than an observation
of unequivocal facts, a certain level of legitimate difference of opinion is inevitable. Differences of opinion among cytopathologists affect diagnostic yield
and must be factored into any assessment of the clinical value of this approach to detection. An irreducible level of interobserver variation is probably
15% but the issue has rarely been addressed. Instead,
the focus has usually been on the adoption of a sin-
Improvement in interobserver variation is not likely
to depend on better education or more consensus, at
least so long as classification schemes remain complicated. A recent study may be revealing in this
regard [221]. The 1998 WHO/ISUP classification
scheme represents a broad consensus of experts in
urologic pathology, as evidenced by their names list-
45
ed in the original publication [105]. The scheme is
well-illustrated and has been presented in many
forums. When a group of practicing pathologists
attempted to use the system, a very high degree of
agreement (91%) was achieved only when the goal
was to distinguish low grade neoplasms (PUNLMP,
low grade carcinoma) from high grade carcinomas
(high grade carcinoma, CIS). In contrast, when the
goal was to distinguish PUNLMP from low grade
carcinoma, interobserver disagreement was 50%.
And this level of interobserver variation occurred
after the three collaborators had spent hours together
educating themselves on the diagnostic features,
viewing slides of the lesions, and creating a diagnostic paradigm. Neither lack of education, sloth, inexperience, nor absence of well-described and wellillustrated “criteria” are likely to account for the
results. If anything, the problem lies in attempting to
achieve more refinement in classification than the
“methodology” can support. The more decision
points a system requires and the closer the distinguishing features between one class and another, the
more likely that disagreements will occur. In the case
of urinary cytopathology, substantial interobserver
agreement can be achieved for high grade neoplasms
because nearly all of the tumor cells manifest nearly
all of the features described and illustrated in the literature. This is not the case for dysplastic or low
grade cells, where many of the cells in any sample
will lack some or most of the features.
fact, there are no reliable criteria for selecting
patients at high risk for upper tract cancers. Routine
IVU is unnecessary at the initial diagnosis of bladder
cancer, but many patients undergo IVU as part of a
hematuria evaluation.
The cytopathologic assessment of urinary specimens
is a valuable means to detect tumor cells in patients
suspected of harboring a “bladder cancer.” Despite
its limitations this approach is currently the single
most efficacious way to monitor patients for clinically important disease.
c) Metastatic Evaluation
b) Staging of the Primary Bladder Tumor
IVU is not useful for staging bladder cancer; however, bladder tumors causing ureteral obstruction are
often muscle-invasive (Level 3, [160,224]). Ultrasound is not utilized for staging because of its limited ability to evaluate the perivesical tissue (Level 3,
[225,226]). Computerized tomography (CT) scan
and magnetic resonance (MR) imaging delineate the
perivesical tissue, but staging accuracy is quite variable, ranging from 40% to 98% (Level 3, [227-229]).
MR is slightly more accurate for staging than CT
(Level 3, [226]).
When pelvic imaging is performed after TURBT,
staging accuracy drops to 32% to 55% because postoperative inflammation mimics the appearance of
tumor infiltration (Level 3, [225,227-229]).
Ultra-fast dynamic MR sequences may be a more
reliable method for distinguishing residual tumor
from postoperative inflammation (Level 3, [230]).
Currently, MR and CT are not accurate enough for
staging of the primary tumor (especially after
TURBT), but they are utilized for assessing the presence of metastases (Level 3, [228]).
The accuracy of MR and CT for staging of the lymph
nodes ranges from 70% to 98% (Level 3, [225,226],
with a false negative rate of 20% to 40% (Level 3,
[225,228]). The main limitation of abdominal and
pelvic imaging is that it cannot detect local or distant
microscopic cancer invasion, which leads to significant understaging (Level 3, [227-229]). Furthermore, routine abdominal and pelvic imaging rarely
alters the management of patients with invasive bladder cancer (Level 3, [228,231]).
4. IMAGING OF BLADDER CANCER AT INITIAL
DIAGNOSIS
a) Evaluation of the Upper Urothelial Tract
Most patients with bladder cancer present with
hematuria; therefore, they often undergo intravenous
urogram (IVU) before the bladder tumor is discovered. Nevertheless, several authors suggest that routine IVU is unnecessary at the initial diagnosis of
bladder tumor because synchronous upper tract
urothelial cancer is rare, occurring in only 0.3% to
2.3% of cases (Level 3, [160,222,223]). The stage,
grade, and volume of the primary bladder cancer do
not correlate with the risk of upper tract cancer;
therefore, these characteristics cannot be used to predict which patients need an IVU (Level 3, [222]). In
The usual metastatic evaluation for invasive bladder
cancer includes chest radiograph, liver function tests,
and alkaline phosphatase (Level 4, [232]). Abdominal and pelvic imaging (CT or MR) is often reserved
for patients with abnormal liver function tests,
advanced local cancer based on TURBT and bimanual examination, or high clinical suspicion of metastasis [231, Level 3; 232, Level 4]. Bone scan is
unnecessary in most cases; however, it should be
considered when alkaline phosphatase is elevated or
bone pain is present (Level 3, [233-235]).
46
5. CYSTOSCOPY
Regarding the number of tumors (or sites), Pagano et
al. reported that 72.5% of 200 patients with superficial bladder tumors had solitary lesions, 11.5% had
between 3 and 5 sites, and 16% had more than 5 sites
[136]. They found that patients with multifocal
tumors were more likely to recur and infiltrate. Abel
et al. studied 107 patients with superficial tumors. Of
107 patients, 65 (61%) had single tumors and 42
(39%) had multiple tumors. Of 65 patients with single tumors, 49 (75%) had pTa tumors compared to
64% of patients with multiple tumors [239]. Lutzeyer et al. reported the progression rates in solitary pTa
and pT1 tumors of 18% and 33% and 43% and 46%,
respectively, for multiple tumors [240].
a) Appearance of the Tumor
Appearance of bladder tumors by cystoscopy is
important for diagnosis and treatment. Information
such as number, size, shape, and location of tumors
is easily obtained. Experienced urologists can determine the degree of difficulty of TUR and decide the
necessity of obturator nerve block immediately after
the first look by cystocope. Utz et al. reported the
features of tumors determined by cystocopy in 1973;
20% of the tumors were on the right lateral wall,
15% on the left lateral wall, 17% on the posterior
wall, and 10% on the trigone [236]. In 31 patients,
the lesions were multiple, but in only 7 patients was
more than 1 wall involved. Twelve cancers (6%)
were discovered in diverticula.
Pagano et al. divided the patients into 3 groups based
on the size of the tumors - diameter less than 1 cm, 1
to 3 cm, and greater than 3 cm (Level 3, [165]). They
found no correlation between the size and the grade,
and the progression of the tumor was not influenced
by the size of the tumors.
Cystoscopically, the appearance of the bladder tumor
can be classified according to characteristics of the
surface and the base of the tumor. Approximately
70% of urothelial tumors are papillary, 10% are
nodular, and 20% are mixed.
Dalesio et al. conducted a randomized clinical trial
of 308 patients with stage T1 cancer to compare the
efficacy of TUR alone or TUR followed by intravesical chemotherapy [241]. Of the 296 patients, 201
(68%) had a largest tumor greater than 2 cm in diameter and the remaining 95 had tumors greater than 3
cm. Those patients with tumors less than 2 cm in
diameter had a marginally lower recurrence rate than
those with tumors greater than 3 cm (P = 0.096).
Similarly, according to the cystoscopic appearance
of the base of tumor, bladder neoplasms may be
pedunculated or sessile tumors. A majority of low
grade urothelial carcinomas are well-pedunculated
tumors.
CIS is a flat lesion in the bladder mucosa and may
appear as a velvety patch of erythematous mucosa,
although quite often it is endoscopically invasive.
b) Fluorescence Endoscopy
White light endoscopy of the lower urinary tract is
limited in detection of bladder cancer. Flat neoplastic urothelial lesions such as dysplasia and CIS can
be concealed in normal-appearing mucosa or nonspecific inflammatory-appearing mucosa. The value
of random biopsies, which were initially recommended when flat lesions are suspected, was challenged by Witjes et al., who showed in a cooperative
study of 1026 unselected patients that biopsies of
normal-appearing mucosa were of little value in
determining a patient’s prognosis (Level 3, [242]).
Inverted papilloma is a benign proliferative lesion
associated with chronic inflammation or bladder outlet obstruction. The appearance of an inverted papilloma is usually a papillary tumor covered by a normal urothelium and may contain an area of cystitis
cystica or squamous metaplasia.
Relatively rare tumors in the bladder, urachal carcinomas have a sharp demarcation between the tumor
and adjacent bladder epithelium, with the tumor
being located in the bladder wall beneath the normal
epithelium. Bladder pheochromocytoma appears as a
submucosal nodule covered by intact urothelium.
The risk of overlooking even papillary tumors is significant. Grimm et al. reported that after transurethral
resection of superficial bladder cancer, residual
tumor has been identified in 33% of cases at repeat
resection (Level 3, [243]). In 28% of the patients
with fractional resection of T1 urothelial carcinoma,
residual tumor was found at the margins of the
resected area (Level 3, [244]).
In contrast to the importance of pathological staging
of tumor by TUR specimens, whether additional
prognostic information can be obtained from cystoscopy remains controversial. Mulders et al. and
Jakse et al. reported that patients with multiple
tumors were more likely to recur than patients with
single tumors [237,238]. Jakse et al. also reported
that wide-based tumors were more likely to be poorly differentiated and grade 3 [238].
Patients with newly-diagnosed, superficial, well- or
moderately-differentiated tumors had significantly
47
less recurrence when the bladder was free of tumor 3
months after the initial resection (Level 3, [245]).
risk of residual tumor after transurethral resection of
urothelial carcinoma is significantly decreased by 5ALA fluorescence endoscopy (Level 3, [262-264]).
For years, methods of labeling urothelial neoplasmas
have been sought [246,247]. Fluorescent photodetection of neoplastic urothelial lesions using 5-aminolevulinic acid was first described in 1994 (Level 2,
[248]). 5-ALA is a precursor of heme biosynthesis.
Following intravesical instillation, 5-ALA induces
selective enhancement of protoporphyrin IX with a
strongly fluorescent dye in the mucosa of neoplastic
lesions. The fluorescence is excited with blue light
(375–440 nm) and becomes visible using an observation filter in the eyepiece of the endoscope for
color contrast enhancement (Level 2, [249]).
One prospective single center randomized Phase III
trial is published, which focuses on the risk of recurrent tumor after transurethral resection with 5-ALA
photodection compared with conventional white
light endoscopy. Recurrence-free survival in the fluorescence group was 91% after 24 months compared
with 70% in the white light group (P = 0.0005). The
adjusted hazard ratio of photodiagnostic versus
white light transurethral resection was 0.29 (95% Cl
0.15 to 0.56) and photodetection proved an independent prognostic factor (Level 3, [265]).
Photodetection using 5-ALA has proved to have high
sensitivity for detecting early stage bladder cancer,
ranging from 87% to 96%. Specificity is less due to
inflammatory lesions (Levels 2 and 3, [250-255]).
These lesions are found especially after intravesical
chemotherapy, BCG treatment, and endoscopic
resection (Level 2, [256]). Photodetection is recommended primarily for evaluation of the untreated
urothelium or if the mucosa has healed after the
treatment. Quantification of 5-ALA-induced fluorescence improves the specifity by 30% without affecting the sensitivity (Level 3, [257]).
Fluorescence cystocopy clearly is superior to the
conventional white light endoscopy. It seems to be
well verified that the risk of residual tumor is
reduced by fluorescence-guided resection. This may
lead to lower recurrence rates, as has been shown in
the first Phase III trial, but this has to be proven in
further studies.
6. TRANSURETHRAL RESECTION
TUMORS (TURBT)
OF
BLADDER
Transurethral resection of bladder tumors (TURBT)
provides diagnostic information and often achieves
therapeutic benefit. The goals of TURBT are to
determine the stage and grade of the tumor (diagnostic) and to resect or fulgurate all grossly visible
tumor when indicated (therapeutic). The technique
for TURBT is based mainly on surgeon experience.
The technique described below is based on a review
by Shelfo and colleagues (Level 4, [266]).
Detection of flat neoplastic lesions that can easily be
missed during white light endoscopy was significantly enhanced by using 5-ALA photodetection. In
comparison to white light cystoscopy, up to 53%
more patients with CIS were found (Level 3, [258]).
Sixty-three patients with cytology positive or suspicious for disease and a negative standard cystoscopy
underwent photodetection. In 51 of these cases
(80.9%), the cytological findings were verified by
fluorescence endoscopy detecting the precise site of
malignancy within the bladder. The 12 remaining
patients from this group did not show positive fluorescence and no positive histology was found in the
random biopsies taken. In all of these cases, neoplastic disease of the upper urinary tract was excluded by
a retrograde pyelography (Level 3, [259]). In order to
improve the diagnostic quality of the procedure, an
ester of aminolevulinic acid, hexaminolevulinate
(HAL), was investigated in a multicentric study. It
was found that photodetection with HAL indentified
28% more patients with CIS than standard cystoscopy (Level 3, [260]).
General, spinal, or epidural anesthesia may be used.
When resecting tumor on the lateral wall, general
anesthesia with neuromuscular blockade may help
prevent obturator nerve stimulation. Place the patient
in the dorsal lithotomy position with the buttocks at
the edge of the table. Pad all pressure points, especially the lateral proximal fibula. Prolonged pressure
on this area can cause neurapraxia of the common
peroneal nerve, resulting in foot drop. Perform a
bimanual examination (preferably with the bladder
empty), by placing one hand in the suprapubic region
and one or two fingers of the other hand in the rectum (for males) or in the vagina (for females). The
bladder and other pelvic organs are palpated between
the two hands. Identify palpable masses and determine whether they are fixed to adjacent structures.
Bimanual examination should also be performed
after TURBT.
Photodetection of neoplasias that were missed under
white light cystoscopy resulted in a change in treatment strategy in 9% (Level 3, [261]). Three prospective randomized studies have clearly shown that the
48
Insert the cystoscope and inspect the entire urethra.
Examine the bladder with the 30 degree and 70
degree lenses. Visualization of the dome and anterior bladder may be enhanced by applying gentle
suprapubic pressure, which moves the bladder wall
closer to the endoscope. Adequate bladder distension
unfurls the folds in the bladder and permits complete
inspection of the urothelial surface. Overdistention
of the bladder should be avoided because this can
induce mucosal hemorrhage. Inspect the interior of
any diverticula and cellules. Note the location and
size of abnormal areas and their relation to the ureteral orifices.
of resection. The third phase is resection of tissue
surrounding the tumor base. Tissue removed during
the third phase determines the status of the lateral
margins of resection. The resected tissue may be
combined and sent to the pathologist as a single
specimen so that the tissue fragments are analyzed
together (collective analysis) or the tissue from each
phase may be isolated and sent as a distinct specimen
so that each phase is analyzed separately (differential
analysis). Some believe that differential analysis
achieves more accurate characterization of the cancer (Level 3, [267,268]), while others believe that
differential analysis is unnecessary (Level 4, [269]).
A trial comparing the accuracy of differential and
collective analysis has not been conducted.
A bladder wash cytology may be obtained before
TURBT by irrigating normal saline through a
catheter, cystoscope sheath, or resectoscope sheath
(barbotage). Bladder wash cytology detects carcinoma in situ in almost all cases (Level 3, [198]), even
when the urothelium appears grossly normal, and
this obviates the need for routine random bladder
biopsies (Level 4, [187]). During barbotage, the
bladder wall can be drawn against the sheath, causing urothelial trauma that may mimic the appearance
of CIS. Therefore, it is best to perform the bladder
wash cytology after complete inspection of the bladder, though the urine collected immediately upon
scope introduction should also be sent for pathologic review.
b) En bloc Resection
The resection loop is approximately 1 centimeter in
diameter. Therefore, tumors less than 1 centimeter
may be resected in one whole specimen (en bloc
resection) using the standard loop. Techniques for en
bloc resection of tumors that are up to 3 centimeters
in greatest dimension have also been described
(Level 3, [270-272]). Proponents of en bloc resection
believe that it may permit more accurate pathological assessment by preventing tumor fragmentation,
by preserving the orientation of the tumor relative to
the bladder wall, and by decreasing cautery artifact
at the tumor base. However, data to support this concept is lacking. A trial comparing staged TURBT and
en bloc TURBT has not been conducted.
Insert the resectoscope sheath in an atraumatic fashion and begin resection. Continuous irrigation may
improve visualization and prevent overdistention of
the bladder. Utilizing a camera and video monitor
can improve visualization by magnifying the image
and reducing eye strain. With a video system, the
surgeon may also experience less cervical stress and
less risk of direct exposure to biohaz-ardous fluids.
There are 2 basic techniques for performing TURBT:
staged and en bloc.
After resection, obtain hemostasis. Then, inspect the
bladder and the ureteral orifices and ensure that all
tumor chips have been removed. The operative
report should include a detailed description of the
procedure including:
1) The appearance (flat, papillary, sessile), number,
approximate size, and location of tumors. The size
of a tumor can be estimated by using the 1 centimeter width of the resection loop as a reference.
a) Staged Resection
Staged TURBT may consist of several phases (Level
3, [267,268]). The first phase is resection of tumor
that protrudes into the bladder lumen. Begin resecting superficially, starting at one side of the tumor and
gradually progressing to the other side. Resect the
next layer of tumor in the same fashion. This process
is continued until the base of the tumor is reached.
The second phase is resection of the base of the
tumor and of a portion of the underlying bladder. Tissue removed during the second phase determines the
depth of invasion and the status of the deep margins
2) The location and approximate depth of resection
(superficial, into muscle, into perivesical fat).
3) Whether all gross tumor was removed or whether
residual gross tumor remained.
4) Whether bladder perforation occurred.
5) Whether the ureteral orifice was resected or intact
at the end of the procedure.
6) The results of the bimanual examination.
49
c) Tumor Resection in Specific Circumstances
include flank pain (Level 3, [280]), urinary tract
infection (Level 3, [277,278]), and deterioration of
renal function (Level 3, [278,281]). Bladder outlet
obstruction may increase the likelihood that reflux
becomes clinically significant (Level 3, [280]).
Reflux increases the occurrence of upper tract
tumors by 15- to 22-fold (Level 3, [281-284]).
Therefore, surveillance of the upper tracts should be
conducted more frequently in patients with reflux an
d a history of bladder cancer (Level 3, [283,284]). It
is unclear whether patients with reflux after TURBT
require treatment; however, they should probably be
treated if they develop pain, recurrent urinary infections, or renal deterioration (Level 3, [285]). Vesicoureteral reflux after TURBT has been successfully
treated with endoscopic injection of a bulking agent
below the intramural ureter (Level 3, [286]).
1. DIFFUSE CIS
Because CIS is treated with intravesical therapy, it is
probably best to biopsy areas suspicious for CIS and
cauterize the affected surface. However, cauterization should be limited in cases when diffuse CIS is
suspected because resection or fulguration of large
areas may cause bladder contracture. If CIS is confirmed on the biopsies, treatment alternatives are
then discussed.
2. MUSCLE-INVASIVE TUMORS
When muscle-invasion is suspected, resect as much
tumor as feasible and enough tissue to verify the
presence of tumor in the muscularis propria. Intraoperative pathology assessment can ensure that sufficient tissue is available to confirm muscle invasion.
If the muscular layer is not evident because of tumor
infiltration, the depth of the muscle may be more
easily identified at the periphery of the tumor (Level
3, [267]). When transurethral resection (alone or in
combination with other bladder-sparing therapies) is
used as a definitive treatment for muscle-invasive
cancer, a deep re-resection can be performed (Level
3, [273]). In this case, resection into the perivesical
fat may be tolerated in order to remove the cancer.
4. TUMORS ON THE ANTERIOR SURFACE
Tumor on the anterior wall may be more easily engaged by counter pressure on the suprapubic region
with the nondominant hand (Level 4, [266], Level 3,
[274]). This maneuver moves the bladder wall closer
to the resectoscope.
5. TUMORS ON THE LATERAL WALL/OBTURATOR
NERVE STIMULATION
Resection of tumors on the lateral wall can stimulate
the obturator nerve, resulting in sudden adduction of
the leg. This abrupt movement can force the resectoscope into the bladder wall and lead to bladder perforation. Methods to reduce obturator nerve stimulation include using general anesthesia with neuromuscular blockade, (Level 4, [266], Level 3, [287,288])
performing obturator nerve block with a local anesthetic (Level 4, [266], Level 3, [288,289]), avoiding
overdistending the bladder [266], lowering the resection current [266], and using intermittent instead of
continuous cautery [266].
6. TUMORS IN BLADDER DIVERTICULA
Tumors in diverticula present several diagnostic and
therapeutic dilemmas. First, the diverticular wall is
thinner than the normal bladder because it lacks a
muscular layer (absent muscularis propria). A thinner wall may increase the risk of perforation when
attempting to completely resect the tumor. Second,
a thinner wall may permit the tumor to invade into
the extravesical tissue more rapidly. Third, the
absence of muscularis propria may make accurate
staging difficult. Some authors suggest that stage
pT2 should be omitted for diverticular tumors, and
that staging should progress from pT1 directly to
pT3 (Level 3, [290]).
3. TUMORS AT THE URETERAL ORIFICE
Extensive cauterization of tumors at the ureteral
orifice can cause distal ureteral stenosis (Level 3,
[274,275]). However, ureteral stenosis is uncommon when cutting current is used (Level 3,
[276-278]). To prevent stenosis of the ureteral orifice, the following techniques have been proposed:
employ exclusively cutting current (Level 3,
[275-278]), perform the resection at maximum controlled speed (Level 3, [275-278]), and control bleeding with focal “pinpoint” light touch coagulation
using low intensity current (Level 3, [275,276,278]).
A temporary ureteral stent may maintain a patent distal ureter during healing; however, it is unclear
whether it reduces the risk of stenosis. Stent placement may be prudent in patients with a solitary kidney or poor renal function (Level 4, [266]). To check
for postoperative obstruction, a functional study
(for example, an intravenous urogram or nuclear
renal scan) is recommended 3 to 6 weeks after
resection of the ureteral orifice (Level 4, [266];
Level 3, [279]).
Resection of the ureteral orifice can lead to vesicoureteral reflux (Level 3, [277,278,280]). In adults,
complications from reflux are uncommon, but may
50
2. REDUCING CAUTERY ARTIFACT
Golijanin and colleagues recently presented a systematic approach to the evaluation and treatment of
diverticular tumors (Level 3, [291]). Based on
bimanual
examination
under
anesthesia,
transurethral resection or biopsy of the tumor, and
pelvic imaging (computerized tomography or magnetic resonance imaging), the diverticular tumors
were classified as noninvasive (Ta or Tis), invasive
but confined to the diverticulum (T1), or invasive
into extradiverticular tissue (Level 3, [291]). The
best treatment options for large, high grade, or
extravesical tumors is probably diverticulectomy,
partial cystectomy, or radical cystectomy (Level 4,
[266], Level 3, [291,292]). For small, low grade, and
noninvasive tumors, transurethral resection or fulguration may be appropriate (Level 4, [266], Level 3,
[291,292]). Intravesical therapy may also be utilized
(Level 3, [291,292]). and may be particularly useful
when CIS is present or when resection of the tumor
is incomplete. Stage pT1 tumors may be treated with
either open surgical excision or transurethral surgery
and intravesical therapy (Level 3, [291]).
Data on preventing cautery artifact is lacking. To
reduce cautery artifact during resection, the surgeon
should use pure cutting current at the lowest possible
setting. Coagulating current should be reserved for
hemostasis after the tissue has been removed. Cold
cup biopsies may be performed prior to resection
when the surgeon prefers to avoid cautery artifact.
e) Role of Repeat TURBT
The management of bladder cancer is dependent
upon an adequate transurethral resection of the bladder tumor (TURBT) and accurate staging and grading of the disease. Most significantly for high grade
Ta and T1 lesions, it is incumbent for the urologist to
assure that the tumor is actually not muscle-invasive,
since this typically changes the treatment options.
Herr retrospectively evaluated the concordance of
the pathological diagnoses between an initial resection and a second TURBT in 150 patients (Level 3,
[294]). The results of the second resection changed
the treatment in 33% of the patients. He importantly
noted the inability to accurately diagnose T1 tumors
without muscle in the specimen. Of 23 patients with
T1 lesions without muscle in the primary resection,
11 (49%) were upstaged to T2 lesions after review of
the second TURBT specimen. A caveat of this study
is that not only did different urologists perform the
first and second TURBTs, but different pathologists
read the first and second bladder tumor specimens.
Dutta et al. similarly reported a 64% risk of understaging T1 lesions when muscle was absent compared to only 30% when muscle was present in the
TURBT specimens (Level 3, [295]).
d) Other Important Considerations
1. AVOIDING BLADDER PERFORATION
Bladder perforation may increase the risk of postoperative hemorrhage, urinary tract infection, and sepsis (Level 3, [293]). The cancer death rate appears to
be higher in patients whose bladder is perforated during TURBT, presumably because tumor cells implant
in the extravesical tissue (Level 3, [293]). Therefore,
avoiding bladder perforation optimizes oncologic
control and minimizes surgical complications.
Methods to prevent bladder perforation include:
• Use caution when resecting a tumor in a diverticulum. The diverticular wall is thinner than the
normal bladder wall.
Other authors have found that primary resection of a
T1 bladder tumor may be inadequate to remove all
tumors. Zurkirchen et al. retrospectively reviewed
those patients who underwent follow-up TURBTs
within 6 weeks of their initial resections (Level 3,
[296]). Thirty-seven percent of patients with initially diagnosed T1 bladder tumors had persistent
tumors on second resection. Grimm et al. similarly
retrospectively reviewed 83 patients who underwent
repeat TURBT a mean of 7 weeks after initial
TURBT (Level 3, [243]). Residual tumor was found
in 33% of cases, including 53% of those with bladder tumors initially diagnosed as T1. On univariate
analysis, both tumor stage and grade were identified
as predictive for residual tumor on restaging
TURBT. Furthermore, after 5 years there was a significant decrease in disease-free survival between
those who underwent a second TURBT and those
• Avoid the obturator reflex. An obturator reflex
generates an abrupt leg movement that can contribute to perforation.
• Avoid bladder overdistention [266]. Overdistention can increase the risk of perforation by reducing the bladder wall thickness and by increasing
the intravesical pressure. A continuous flow resectoscope may help prevent overdistention.
• Administer adequate anesthesia. Adequate
anesthesia reduces patient movement during the
procedure and may help relax the bladder.
• Avoid deep resection at the base of low grade,
stage Ta tumors. Deep resection of tumors that
appear superficial is probably unnecessary and
may increase the risk of bladder perforation [266].
51
who did not (63% and 40%, respectively). Brauers et
al. evaluated 42 patients with moderate or high grade
T1 bladder tumors and reported that 24% of patients
were upstaged to T2 or Tis on restaging TURBT
(Level 3, [297]). Schips et al. prospectively evaluated the findings at first and second TURBT for
patients with high grade T1 bladder tumors and
found residual disease in over 50% of patients (Level
3, [298]). Both multifocality and tumor grade
increased the risk of finding residual tumor on second TURBT. While 76% of patients with a solitary
T1 lesion at first TURBT had a negative second
TURBT, only 53% of those with multifocal T1
lesions had a negative repeat TURBT. Moreover,
73% of those with papillary-appearing T1 lesions at
first resection had a negative repeat TURBT, compared to only 47% of those with solid-appearing T1
lesions. Klan et al. retrospectively evaluated 69
patients with stage T1 lesions on TURBT, of whom
46 agreed to a repeat TURBT within 2 weeks of initial resection (Level 3, [244]). In 20 patients (43.5%),
tumor was found at repeat TURBT. The authors
noted that those who initially underwent a fractionated TURBT—all visible tumor is resected first, and
the tumor margin and base are taken as separate samples—had a lower incidence of residual tumor on
repeat TURBT than in those who underwent a standard TURBT.
ion is that this should be performed within 1 to 4
weeks following the initial resection.
f) Role of Random Bladder Biopsies
Bladder cancer is frequently multifocal and CIS or
dysplasia can be found in bladder mucosa that is distant from the tumor in apparently normal-looking
areas. It is well-known that the presence of CIS is a
significant risk factor for tumor recurrence and progression and that therapeutic options need to be modified accordingly [301,302].
During TURBT, any abnormal appearing urothelium
should be biopsied. However, the role of routine random bladder biopsies is still controversial [302-304].
In a European Organization for Research and Treatment of Cancer (EORTC) study, 393 patients with
solitary Ta and T1 tumors underwent biopsy of normal appearing mucosa, and CIS was detected only in
6 patients (1.5%). In another EORTC study, 602
patients with multiple or recurrent Ta and T1 tumors
(high-risk group) underwent multiple random bladder biopsies. Only 3.5% showed CIS in the random
biopsies. Only 1 patient was found to have T2 disease unexpectedly and underwent cystectomy. The
study showed that finding additional Ta tumor or CIS
in the high-risk group did not change the clinical
treatment in most cases and hence the authors concluded that routine random bladder biopsies are not
necessary [305].
There are no specific studies available at present
regarding the optimal timing of second resection.
However, the consensus opinion is that this should
be performed within 1 to 4 weeks following the initial resection. May et al. and Sanchez-Ortiz et al.
reported that delay of more than 12 weeks in muscleinvasive bladder cancer leads to significant upstaging of the disease (Level 3, [299,300]). Hence,
undue delay in second resection should be avoided.
Taguchi et al. reported that CIS was detected in
14.5% of 83 patients [306]. Fujimato et al. performed random bladder biopsies in 100 consecutive
patients [304]. In 8 of 100 patients, bladder cancers
were detected in the biopsy specimens. Three cases
were Ta and 5 were Tis. All of the 5 patients (17.9%
[5/28]) with CIS in their biopsy specimens had multiple papillary broad-based tumors and positive urinary cytology. None of the 72 patients who had a
solitary tumor, pedunculated tumor, or negative urinary cytology had concomitant CIS. They conclude
that random bladder biopsies are necessary only for
patients with multiple papillary broad-based tumors
and positive urinary cytology. May et al., in a large
series of 1033 patients, reported finding urothelial
tumor on random bladder biopsies in 12.4% [302].
This included 7% with Ta, 4% with CIS, 1% with T1,
and 0.1% with T2. More importantly, the treatment
was altered in 6.8% of patients because of the random biopsy findings.
In summary, these case control studies show that the
risk of upstaging on second TURBT is at least 30%
if muscle is present in the specimen and even higher
if muscle is not present (Level 3, [294,295]). Further,
the risk of residual tumor on second TURBT is also
significant. Even for solitary, papillary-appearing
tumors the risk is 24% to 27%, and it is higher for
multifocal, nonpapillary lesions (Level 3, [243,244,
294,296,298]). Because of these significant rates, it
is recommended that a second TURBT be performed
in all patients with high grade Ta or any T1 urothelial carcinoma. Separate tumor base and margin
biopsies decrease the chances of under staging (Level
3, [244]). Although no evidence regarding the timing
of a second TURBT is available, the consensus opin-
The potential risk of tumor implantation and tumor
recurrence due to random bladder biopsy is contro-
52
tectomy for bladder cancer [313]. Of 80 patients with
CIS in the bladder, 31% had concomitant prostatic
urethral involvement, whereas only 4.5% of the 112
with no evidence of CIS had prostatic urethral
involvement. Likewise, 35% of the 72 patients with
multifocal tumors had concomitant prostatic urethral
involvement with carcinoma, whereas only 4.2% of
the 120 with solitary tumor had prostatic urethral
involvement. In the multivariate logistic regression
model, the odds of prostatic urethral involvement
were 12- and 15-fold greater when CIS and tumor
multifocality were present, respectively.
versial. Levi et al. reported that cold cup bladder
biopsy increased the risk of tumor recurrence in the
presence of CIS [307]. On the contrary, Mufti et al.
did not find tumor implantation as a risk factor for
subsequent new tumor development [303]. Biopsy
by wire loop electrocautery may not contribute to
subsequent CIS but random bladder biopsy with cold
cup biopsy forceps poses a possible risk for CIS, and
hence the biopsy site should be thoroughly cauterized [307].
In summary, the role of random bladder biopsies is
still controversial. Though there is no strong evidence to support either way, the consensus opinion is
that the random bladder biopsy does not change the
clinical treatment in most cases and hence is not recommended on a routine basis. It is recommended in
cases with positive urine cytology and normalappearing mucosa. In cases where random biopsies
are indicated, there is no evidence to support the
location and the number of biopsies that should be
performed. However, it is common practice to perform 4 quadrant biopsies involving the anterior wall,
dome, and posterior and lateral walls. In patients
who elect to undergo partial cystectomy, random
bladder biopsy is advisable.
Cystoscopy is a valuable tool in identifying prostatic
involvement. Solsona et al. reported that in more
than 75% of patients with prostatic urothelial carcinoma, the tumor was macroscopically visible on cystoscopy [314]. Nixon et al. reported that 97% of
patients with prostatic urothelial carcinoma showed
abnormalities of the prostatic urothelium on cystoscopy [313].
Sakamoto et al. reported that in 29 of 31 patients
(93.5%) with urothelial carcinoma of the prostate,
the disease was located at the 5 and 7 o’clock positions of the verumontanum [315]. Furthermore, at
this location deep stromal invasion was high at
57.7% compared to other locations. Hence, they
emphasized that a transurethral electrocautery loop
biopsy of the prostate at the 5 and 7 o’clock positions
of the verumontanum substantially improved the
detection of prostatic involvement. Yield from the
cold cup biopsy is inferior to resection biopsy.
Fluorescence endoscopy using 5-alpha aminolevulinic acid increases the chances of detection of
CIS. Zaak et al. found that 52.8% of specimens with
CIS had been missed under conventional white light
cystoscopy [258]. Fluorescence endoscopy may
become a useful tool for detecting CIS and may alter
the practice of random bladder biopsy. The role of
fluorescence endoscopy is discussed in detail later in
this chapter.
In patients with high grade urothelial carcinoma of
the bladder requiring intravesical treatment, it is
imperative that the status of prostatic urothelium is
assessed accurately. Those patients with urothelial
carcinoma of the prostate will require formal bladder
neck resection to facilitate effective contact between
the intravesical medication and prostatic urethra.
g) Role of Prostatic Urethral Biopsy
Urothelial carcinoma (TCC) of the prostatic urethra
in patients with bladder cancer significantly influences the prognosis and affects the choice of therapeutic modality. The reported incidence of primary
prostatic urothelial carcinoma is low at 1% to 4%
[308,309]. However, the incidence of concomitant
urothelial carcinoma of the prostate and bladder is
high but variable, ranging from 7% to 43% [310312].
Studies have shown that presence of prostatic urothelial carcinoma alone is not a contraindication for
neobladder reconstruction and not an indication for
synchronous urethrectomy [316,317]. However, preoperative knowledge of prostatic involvement helps
the surgeon to counsel the patient and modify surgical procedures accordingly.
Nixon et al. reported prostatic urethral involvement
in 30 of 192 patients (15.6%) who underwent cys-
53
RECOMMENDATIONS
I. EPIDEMIOLOGY
with prognosis, subsequent studies have shown differences in prognosis and progression from low
grade papillary carcinoma (Grade B).
2. Substaging of T1 tumor based on muscularis mucosa
invasion should not be universally adopted or advocated to pathologists (Grade D).
3. For pT1 tumors, the presence or absence of muscular propria should be reported (Grade B).
4. For pT1 tumors, pathologists should provide assessment of the depth of lamina propria invasion or
extent of the disease (Grade B).
5. There is little evidence supporting the substaging of
T2 tumor based on the depth of muscularis propria
invasion. Distinction between pT2a and pT2b tumor
is unnecessary (Grade B).
6. Tumor size should be included in the subclassification of pT2 tumors (Grade C).
7. Distinction between pT3a and pT3b tumor is unnecessary (Grade C).
8. Subclassification of patients who have prostatic urethral involvement, based on the presence or absence
of stromal invasion, is recommended (Grade D).
III. DIAGNOSIS
1. Currently there is no evidence available to show that
bladder cancer screening is helpful in improving the
survival. However, further studies are warranted to
evaluate the true value of bladder cancer screening
(Grade C).
2. Screening should probably be confined to patients at
high risk for bladder cancer (Grade C).
3. Screening may consist of a yearly urine cytology and
dipstick for hematuria (Grade C).
4. There is no correlation between the number of red
cells per high power field seen on urine microscopy
and the diagnosis of bladder cancer (Grade B).
5. Nearly all patients with bladder cancer diagnosed on
cystoscopy have either some form of microhematuria or macroscopic hematuria. Hence, patients with
microscopic or macroscopic hematuria require further evaluation such as flexible cystoscopy (Grade
D).
6. Microscopic hematuria in patients with bladder cancer is variable and intermittent and hence a single
negative urinalysis for hematuria does not exclude
bladder cancer (Grade C).
7. In patients with irritative voiding symptoms such as
dysuria, frequency, and urgency, bladder cancer, particularly carcinoma in situ, must be ruled out (Grade
C).
1. For the geographical and temporal comparison of
bladder cancer incidence rates, it is crucial to separate low grade Ta tumors from high grade CIS and
pT1 or higher tumors (Grade C).
2. In epidemiological studies on risk factors for bladder cancer, it is advised to distinguish low grade Ta
tumors from high grade CIS and pT1 or higher
tumors (Grade C).
3. The risk of bladder cancer among workers in highrisk industries should be monitored continuously. If
specific plants are suspected, the identification of the
causative agent should be started immediately, preventive measures should be taken, and exposed
workers may have to be screened for bladder cancer
for at least 2 decades (Grade D).
4. Both epidemiology and toxicology studies should
evaluate the role of hair dyes for the development of
bladder cancer. Epidemiologists should agree on
(and validate) a standard questionnaire for exposure
to hair dyes (Grade D).
5. Through international collaboration, families with at
least 3 first degree relatives with bladder cancer
should be collected for the mapping and identification of bladder cancer susceptibility genes (Grade
D).
6. Consensus should be reached over a screening protocol for unaffected members of such bladder cancer
families. Until then, it is suggested to start screening
at the age of 40 or 5 years earlier than the age of the
youngest patient in the family (Grade D).
7. Little is known about lifestyle and constitutional factors in relation to prognosis. Therefore, future epidemiological studies should include follow-up data in
order to learn more about the effects of these factors
on prognosis (Grade D).
8. Future studies on the role of genetic polymorphisms
and their modifying effect of lifestyle risk factors
should take a more systematical high-throughput
approach instead of a SNP by SNP approach. International collaboration will be necessary to reach sufficient power for such studies while avoiding many
false positive associations (Grade D).
II. STAGING AND GRADING
1. The WHO/ISUP, now the WHO 2004, should be the
only classification system used to diagnose bladder
lesions. Although initially there had been conflicting
reports of how well the category of papillary urothelial neoplasm of low malignant potential correlates
54
8. It is recommended that the cytopathologist should
use uniform nomenclature; currently, the 1998
WHO/ISUP Consensus classification is widely
accepted (Grade C).
9. Bladder wash cytology provides better diagnostic
yield than voided urine cytology (Grade B).
10. When a cystoscopy is performed, the residual urine
should be collected for cytology. A thorough cystoscopy with minimal manipulation should be performed, which should be followed by a formal bladder
lavage. Both specimens should be sent for cytopathology (Grade D).
11. Urine cytology is best used for the follow-up of
patients with urothelial neoplasms in order to diagnose high grade tumor recurrence (Grade C).
12. Routine IVU is unnecessary in the initial assessment of bladder cancer; however, many patients
undergo this examination as part of a hematuria
evaluation (Grade B).
13. For invasive bladder tumors,
a. Metastatic evaluation should include chest
radiograph, liver function tests, and alkaline
phosphatase (Grade C).
b. Abdominal and pelvic imaging (MR or CT) is
not accurate for staging of the primary bladder
tumor, but may be useful when metastatic
disease is suspected. (Grade B).
c. Bone scan is unnecessary in all cases, but it
should be performed in the presence of bone
pain or elevated alkaline phosphatase (Grade
B).
14. The shape, size, and location of the tumor should be
documented explicitly as this provides important
prognostic information (Grade C).
15. Carcinoma in situ may present as velvety erythematous patches. The endoscopist should specifically look for these changes and all suspicious
lesions should be biopsied (Grade C).
16. Appearance of the base of the tumor, whether sessile or pedunculated, should be documented, as this
finding often predicts the invasiveness of the tumor
(Grade C).
17. Fluorescence cystoscopy improves the detection
rates of carcinoma in situ (Grade B).
18. Fluorescence-guided transurethral resection of
bladder tumor decreases the chance of residual
tumor (Grade B).
19. Though fluorescence cystoscopy appears promising, further multicentric studies are required
before it can be accepted in to routine clinical practice (Grade C).
20. At the present time, there is insufficient information to recommend a specific resection technique or
method of pathologic evaluation of TURBT specimens. Urologists and pathologists should select
systems with which they feel comfortable (Grade
D).
21. During TURBT, complete tumor resection should
be attempted except for diffuse carcinoma in situ
(Grade C).
22. During TURBT, bladder perforation should be avoided (Grade C).
23. When resecting the ureteral orifice, cutting current
should be used. Avoid coagulation of the ureteral
orifice. Three to 6 weeks after resecting the ureteral orifice, obtain a functional study to check for
stenosis (Grade C).
24. Aggressive resection of a tumor in a bladder diverticulum can lead to perforation. Low grade, noninvasive tumors in a diverticulum may be treated by
transurethral resection or fulguration with or
without intravesical therapy (Grade C).
25. A second TURBT should be performed in all
patients with a high grade Ta lesion or any T1
lesion (Grade B).
26. Separate tumor base and margin biopsies should be
performed during TURBT (Grade C).
27. The suggested optimal timing of repeat TURBT is
within 1 to 4 weeks after the first resection (Grade
C).
28. Routine random bladder biopsies are not recommended (Grade C).
29. Patients with positive urine cytology and normal
bladder should undergo random bladder biopsies
(Grade B).
30. In patients undergoing partial cystectomy, random
bladder biopsies are recommended (Grade C).
31. If cold cup biopsies are performed, the biopsy site
should be cauterized thoroughly (Grade C).
32. Routine prostatic urethral biopsy is not indicated.
Prostatic urethral resection biopsy is indicated in
cases of multifocal urothelial carcinoma of the
bladder, CIS, and visible abnormalities of the prostatic urothelium (Grade B).
33. Prostatic urethral biopsies should be performed
using electrocautry loop resection including the 5
and 7 o’clock positions of the verumontanum
(Grade B).
55
workers: a meta-analysis. Occup Environ Med 2002;59(10):655663.
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64
Committee 2
Cytology And Tumor Markers:
Tumor Markers Beyond Cytology
Chair
V. B. LOKESHWAR (USA)
Members
T. HABUCHI (JAPAN)
H. B. GROSSMAN (USA)
W. M. MURPHY (USA)
G. P. HEMSTREET, III (USA)
S. H. HAUTMANN (GERMANY)
A. V. BONO (ITALY)
R. H. GETZENBERG (USA)
P. GOEBELL (GERMANY)
B. J. SCHMITZ-DRÄGER (GERMANY)
M. MARBERGER (AUSTRIA)
J. A. SCHALKEN (NETHERLANDS)
E. MESSING (USA)
Y. FRADET (CANADA)
M. J. DROLLER (USA)
65
CONTENTS
I. STANDARD CARE FOR BLADDER
CANCER DETECTION AND
SURVEILLANCE
V. URINE CYTOLOGY: THE
STANDARD NONINVASIVE
BLADDER TUMOR MARKER
1. DETECTION
VI. BLADDER TUMOR MARKERS
FOR DIAGNOSIS AND
MONITORING RECURRENCE
2. SURVEILLANCE
II. BLADDER TUMOR MARKERS:
WHY DO WE NEED THEM?
1. SOLUBLE URINE MARKERS
1. TUMOR MARKERS
SCREENING
AND
BLADDER CANCER
2. TUMOR MARKERS
RECURRENCE
AND
BLADDER CANCER
2. CELL-BASED MARKERS
VII. COMPARATIVE ANALYSIS OF
BLADDER TUMOR MARKERS
(2000-2004)
III. IDEAL TUMOR MARKER
VIII. PROGNOSTIC MARKERS FOR
BLADDER CANCER
1. TECHNICAL SIMPLICITY OF DETECTION
2. RELIABILITY
1. CHROMOSOMAL ALTERATIONS AND ALLELIC DELETION (LOSS OF HETEROZYGOSITY)
3. STATISTICAL PARAMETERS FOR EVALUATING
MARKER EFFICIENCY
4. BIOCHEMICAL MARKERS AND
MA OF EARLY DETECTION
THE
2. ONCOGENES
DILEM-
3. TUMOR SUPPRESSOR GENES
4. CELL CYCLE REGULATORS
IV. GOOD CLINICAL PRACTICE IN
MARKER DEVELOPMENT
5. ANGIOGENESIS-RELATED FACTORS
6.EXTRACELLULAR MATRIX, ADHESION
MOLECULES, CELL SURFACE MARKERS,
AND RELATED PROTEINS
1. AIMS OF MARKER STUDIES
2. PHASES OF MARKER STUDIES
3. IMPLEMENTATION
DEVELOPMENT
OF
PHASES
OF
X. OVERALL SUMMARY
MARKER
RECOMMENDATIONS
REFERENCES
66
Cytology And Tumor Markers:
Tumor Markers Beyond Cytology
V. B. LOKESHWAR
T. HABUCHI, H. B. GROSSMAN , W. M. MURPHY, G. P. HEMSTREET, III, S. H. HAUTMANN,
A. V. BONO, R. H. GETZENBERG, P. GOEBELL, B. J. SCHMITZ-DRÄGER, M. MARBERGER,
J. A. SCHALKEN, E. MESSING, Y. FRADET, M. J. DROLLER
that recur may be of higher grade or stage. Thus,
patients with bladder cancer usually undergo 3- to 6month surveillance.
The search for finding new cancer diagnostic tests or
improving existing ones is driven by the appeal of
being able to detect every symptomatic and asymptomatic cancer patient, monitoring tumor recurrence,
and predicting prognosis. If the diagnostic test or
marker is noninvasive, reliable, and inexpensive, it
will significantly improve the clinical applicability
of the marker. In case of bladder cancer, there is an
impetus for developing an accurate and noninvasive
bladder tumor marker(s) because such a marker(s)
could be an important adjunct in screening, initial
diagnosis, surveillance for recurrence, detection of
early progression, and prediction of prognosis [1].
Unlike prostate cancer, bladder cancer is almost
never found as an incidental cancer on autopsy [2].
Patients with bladder cancer present themselves to
urologists with symptoms such as painless hematuria
in the absence of any urinary tract infection and irritative voiding [3,4].
Cystoscopy, the gold standard for the detection of
bladder cancer, is invasive and relatively expensive
(Medicare reimbursement cost in the US: $200$300) [7]. In fact, due to the lifelong need for recurrence monitoring by cystoscopy and the treatment of
recurrent tumors, the cost per bladder cancer patient
from diagnosis to death is the highest among all cancers ($96,000 to $187,000 per patient in the United
States) [8].
Voided urine cytology is a highly specific, noninvasive adjunct to cystoscopy (Figure 1). It has good
sensitivity for detecting high grade bladder tumors,
This mode of detection may be acceptable for the
approximately 70% of urothelial carcinomas that are
low grade papillary tumors, which have little propensity to invade and metastasize [1,3,5,6]. However,
the majority of patients with high grade bladder cancer, at the time of initial presentation, have tumors
that invade the lamina propria (stage T1) and beyond
[1,3-6]. These patients have a high risk of developing
distant metastasis and death despite aggressive treatment of the disease. In these patients, early detection
of bladder tumors, before they become muscle–invasive, will improve survival. Bladder tumors recur
frequently; typically 40% to 80% of patients with
bladder cancer will have a recurrence within 3 years
following initial treatment [5]. Furthermore, tumors
Figure 1. Positive cytology
67
but has poor sensitivity to detect low grade disease.
Furthermore, the accuracy of cytology depends upon
the reviewer’s expertise, and it is relatively expensive and not readily available in all countries. Thus,
a noninvasive, highly sensitive and specific marker(s) for detecting bladder cancer would decrease the
morbidity associated with cystoscopy, improve
patient quality of life, and decrease costs by substituting a less expensive, noninvasive test for the more
expensive endoscopic procedure.
scopes [10]. It is helpful to draw bladder diagrams
showing the number and extent of lesions. Bimanual
examination under anesthesia (EAU) is useful in
staging. The finding of a 3-dimensional mass on
EUA after transurethral resection indicates the presence of extravesical spread.
In other cases, the detection of a superficial bladder
tumor is the result of an intravenous urography
(IVU) performed for various reasons when the late
cystogram shows a filling defect within the bladder,
in the case of papillary tumors. This exam cannot,
however, diagnose a CIS. Once the clinical diagnosis
is made, the rationale for performing an IVU is to
exclude an obstructive uropathy and upper tract papillary tumors [11]. However, personal experience
suggests that its routine use may be neither necessary
nor cost-effective.
In this review on markers, cytology, and molecular
biology, the panel presents a critical analysis of the
recent literature and provides recommendations on
various areas in bladder cancer management where
markers will be useful, requirements of an ideal
bladder tumor marker, and different tumor markers
that are being evaluated for bladder cancer diagnosis,
surveillance, and prognostic predictions.
The further step in diagnosis is the pathologic examination of resected specimens performed on productive or flat suspicious lesions. Pathology definitively
confirms the diagnosis and is mandatory for the correct staging of the disease.
I. STANDARD CARE FOR BLADDER
CANCER DETECTION AND
SURVEILLANCE
2. SURVEILLANCE
Because of the frequency of recurrence, endoscopic
surveillance is essential after tumor resection, intravesical prophylaxis or treatment, and during the maintenance prophylaxis period. Surveillance consists of
periodic endoscopies. Schedules of endoscopies vary
according to patients’ risk factors. The schedule recommended by the EORTC for patients with low- to
intermediate-risk disease is cystoscopy at 3-month
intervals for the first 2 years, at 4-month intervals for
the next 2 years, and yearly thereafter. This schedule
also applies to patients in whom no recurrence is
seen during the follow-up. In case of recurrence, the
follow-up starts again with the same scheme adopted
after the first diagnosis and might even be modified
according to the recurrence patterns and pathology.
This is because a tumor belonging to the low-risk
category can progress in grade or stage or both. For
example, a superficial Ta lesion may recur and
progress toward submucosa infiltration [T1] and, in
addition, CIS may appear. The duration of surveillance is debated: in some centers lifelong follow-up
is recommended. For the high-risk group, an early
re-TURBT or bladder mapping is frequently performed (1-3 months), and control cystoscopies are
continued at 3-month intervals.
1. DETECTION
Bladder cancer may be diagnosed incidentally or
because of symptoms. The main symptom of bladder
cancer is hematuria, but in some patients irritative
symptoms are present from the very beginning. Incidental cancer is usually found on ultrasound, performed either for hematuria or irritative symptoms,
or for screening or symptoms unrelated to the urinary
tract. Ultrasound reveals filling defects, informs
about the postvoid residual urine, and shows some
upper tract patterns. It may give some information
about bladder capacity, useful to suspect the presence of carcinoma in situ (CIS) [9].
The clinical diagnosis of bladder cancer is usually
made by flexible or rigid cystoscopy. Techniques of
rigid and flexible cystoscopy are intuitively different. The observer accustomed only to rigid scopes,
which offer various angles of observation, may be in
some way disoriented with flexible instruments that
have zero degree optics only. The main difference is
that flexible scopes are active instruments because
their tip curvature can vary between +210 to –120
degrees, allowing an easy exploration of all vesical
areas. The limit of these types of instruments is that
the irrigation channel is of small diameter, and,
therefore, in the presence of hematuria the observation can be more difficult in comparison to rigid
The main rationale for such strict follow-up procedures is the natural history of the disease. The vast
majority of cases, which at first observation are
68
defined as “superficial” (70%-80%), show a high
rate of recurrence, varying from 40% to 80% [12].
For instance, the mean 5-year recurrence rate for
low-risk patients treated with transurethral resection
alone is 46%, but it can reach 80% if the patients are
followed for about 20 years [13]. The assumption is
that frequent cystoscopies allow the treatment of the
recurrences at a very early stage, thus lowering the
further recurrence rate and possibly reducing the progression to muscle-invasive disease. Rates of progression of superficial disease is variable, again
depending on the tumor category at first presentation, being about 5% for TaG1 tumors and 20% to
50% for T1 and G3 tumors [14,15]. Endovesical prophylaxis with chemotherapeutic agents increases the
disease-free intervals and time to progression in progressive disease, but does not alter the progression
rate and survival [16]. On the contrary, BCG prophylaxis and treatment act favorably in that sense in
cases with high-risk tumors [17].
before they become invasive (i.e., detection at stages
≤ T1b) would result in improved prognosis [2,5]. The
prevalence of bladder cancer in the general population is low (0.001%) [19]; however, it increases with
age. In prospective community screening studies the
prevalence of bladder cancer among asymptomatic
men above the age of 50 is about 0.67% to 1.13%
[20-27]. Given that high grade bladder tumors
account for about 15% to 30% of all bladder tumors,
the prevalence of high grade bladder tumors in the
general population would be even lower. Thus,
screening the whole population for bladder cancer,
with the possibility of detecting too many false positives (each requiring an expensive work-up), would
not be cost-effective.
Bladder cancer screening may be cost-effective
among individuals who are at a higher risk for bladder cancer. In population cohort studies, cigarette
smoking; occupational exposures to aniline dyes,
aromatic amines, benzidine, and arsenic; parasitic
infections (e.g., Schistosoma haematobium), chronic
bacterial infections, chronic catheterization, and possibly even geographical region (such as Northeast
United States vs. Western United States), have been
shown to increase the risk for bladder cancer [2834]. The risk for bladder cancer is even higher when
smoking is combined with other known bladder carcinogens (e.g., > 80 µg arsenic per day in drinking
water of smokers) or genetic polymorphisms [35].
For example, polymorphisms in N-acetyl transferase-2 (NAT-2; slow acetylator phenotype), glutathione-S-transferase (GSTM1 null phenotype), and
manganese superoxide dismutase genes increase the
risk for developing bladder cancer among smokers
[36,37]. The mean time for the development of bladder cancer, following exposure to bladder carcinogens, is about 18 years [2]. Therefore, early detection
of bladder cancer prior to the occurrence of muscleinvasive disease may be possible if a single or panel
of bladder tumor markers is used for screening the
high risk population.
As far as imaging during the follow-up is concerned,
its validity is questioned. In fact the rate of upper
tract recurrences is reported low, at less than 2%
[18]. Imaging can be useful when multiple resections
of recurrent low grade tumors have been performed
to assess bladder retraction due to scars and its
impact on the upper tract.
Summary
Standard care of bladder cancer detection includes
cystoscopy and pathologic examination of biopsy
specimens. Standard care of bladder cancer surveillance consists of periodic cystoscopies, schedules of which vary according to the risk factors
of the disease.
II. BLADDER TUMOR MARKERS:
WHY DO WE NEED THEM?
When using a bladder tumor marker for screening, it
is essential that the marker have a low false positive
rate. This will avoid unnecessary anxiety to patients
and expensive work-up incurred due to false positive
results. One of the possible ways to identify false
positive results would be to have the knowledge of
conditions and diseases that give rise to a false positive result on a particular marker, and then screening
the population for those conditions along with
screening for the tumor marker. For example, when
screening a population for bladder cancer using
A noninvasive and accurate bladder tumor marker
may be used for bladder cancer screening and recurrence monitoring.
1. TUMOR MARKERS
SCREENING
AND
BLADDER CANCER
A bladder screening program, like any other cancer
program, should be feasible, inexpensive, and accurate, and should promote early detection. In case of
bladder cancer, detection of high grade tumors
69
hemoglobin dipstick (detects hematuria), information on the history of or active episodes of stone disease, urinary tract infection, cystitis, etc., would be
useful to identify false positive results. In a bladder
cancer screening study, involving 401 Department of
Energy workers who had a possible exposure to
bladder carcinogens, the majority of the positive
cases on the BTA-Stat test had an abnormal urinalysis (i.e., 2+ to 3+ protein on dipstick, microhematuria, presence of leukocytes, history of cystitis, and
others) and cystoscopy revealed no evidence of bladder cancer in some of them [38].
weeks [27]. In this trial, the prevalence of bladder
cancer in the entire cohort was 0.69%, but among
men with hematuria it was 3%. The benefits of repeat
hematuria testing were evaluated in a large community screening trial by Messing et al. In this study,
1055 men who were negative on first hematuria 14day testing protocol were solicited for retesting in a
second 14-day testing protocol after 9 months. The
compliance rate in the second phase of the study was
much higher, at 81.1% [24]. The prevalence of bladder cancer in phase II of the study in the total population was 0.82%. However, in the hematuria-positive individuals it was 18.4%. If the results of both
first time detection of hematuria (Phase I) and Phase
II studies are combined, the frequency of bladder
cancer detection among hematuria-positive patients
increases to about 22% [8]. In several of these community screening trials, the detection of bladder cancer by hemoglobin dipstick was found to be independent of tumor grade [20-27], suggesting that if
the hematuria 14-day screening protocol is conducted at regular intervals among individuals above the
age of 50, it may result in early detection of bladder
cancer.
Currently, the data on the feasibility, accuracy, and
cost analysis, as well as the challenges of bladder
cancer screening, are available from a series of community-based hematuria detection trials [20-27]. For
example, in an initial study of 533 individuals over
the age of 50, Messing et al. evaluated the efficacy of
hemoglobin dipstick self-testing once a week for 1
year to detect bladder and other urologic malignancies [21]. The compliance rate in this study (individuals who completed the 1-year testing protocol and
the questionnaire on health and sociodemographic
information) was 44%. Out of the 44 patients who
had hematuria, 5 were subsequently detected to have
bladder cancer and 3 to have renal cell carcinoma.
Thus, although the prevalence of bladder cancer in
the entire study population was 2.13%, in patients
with hematuria it was fivefold higher (11.4%). Interestingly, in this study, among the individuals who
declined to participate, 4 urologic cancers were
detected 18 to 30 months after completion of the
study, suggesting that hematuria screening offers an
early detection advantage [23]. In a subsequent
study, Messing et al. solicited 2932 individuals, out
of which 1736 agreed to a 14-day hematuria testing
protocol and 1340 individuals finally completed the
study [20]. In this study, the prevalence of bladder
cancer in the total population, 0.67%, was lower than
what was observed in the earlier yearlong weekly
hematuria testing protocol. The prevalence of bladder cancer among patients with hematuria (3.2%)
was also lower than that observed in the 1-year protocol. One of the reasons for this difference could be
that patients with urologic malignancies have intermittent hematuria, and, therefore, the chance of
detecting it would be higher if testing was conducted
over a longer period of time. In a screening trial of
578 men over the age of 60, Britton et al. found that
13% of the men were positive for hematuria on a single dipstick test, and an additional 9% were detected
when testing was continued once a week for 10
Contrary to the findings of Messing et al. and Britton
et al., Hiatt et al., in an epidemiological retrospective
outcomes study involving 20 571 men aged 35 years
or older and women aged 55 years or older, found
that the relative risk of urologic cancers was not significantly elevated among individuals positive for
asymptomatic microhematuria when compared to
those with negative results [39]. The sensitivity and
specificity of a single dipstick urinalysis for microhematuria to indicate urologic cancers within 3 years
were 2.9% and 96.7%, respectively. Based on these
results, the authors conclude that screening for
microhematuria among asymptomatic men is not
recommended. However, since hematuria is intermittent among patients with urological cancers and data
show that a substantial percentage of individuals
with a first negative test show a positive test result
during subsequent testing, the results based on a single hematuria dipstick test may not be accurate
[27,28,39].
Cost analysis for bladder cancer screening was also
performed at the end of several of the above discussed screening studies. Messing et al. reported that
the average cost of phase I screening, per participant,
was between $52.32 and $90.96 [20,21]. However,
the cost of phase II screening was low, at $22.76. The
average cost per bladder cancer detected was
$12,960 in Phase I screening and $2,783 in Phase II.
70
Since hematuria also detects other malignancies, the
cost per serious disease found is even lower, $1,935
in Phase I and $1,299 in Phase II [24]. These cost
comparisons compare with other mass screenings for
diseases such as breast cancer [24]. However, it
should be noted that the cost of hematuria screening
might be higher than what was predicted nearly 10
years ago when these studies were conducted. It is
also noteworthy that none of the bladder tumor
markers available today are as inexpensive as the
hemoglobin dipstick test, and, therefore, the cost of
bladder cancer screening using other bladder tumor
markers could be higher depending upon the number
of false positive cases and the need for repeating the
test due to spurious results.
Summary
The use of tumor markers to screen the general
population might not be cost-effective due to the
low prevalence of bladder cancer in the general
population. Screening of high-risk populations,
including populations above the age of 50 (using
hematuria detection) may be cost-effective and
can offer an early detection advantage. More studies with accurate markers are needed to establish
the role (if any) of tumor markers in bladder cancer screening.
2. TUMOR MARKERS
RECURRENCE
One prospective cohort study evaluated the usefulness of bladder tumor markers for screening high
risk populations. Hemstreet et al. assessed the risk
for the development of bladder cancer in a group of
1788 Chinese workers who were exposed to benzidine by developing a biomarker profile [40]. This
biomarker profile included the analysis of DNA
ploidy, G-actin, and tumor-associated antigen P-300.
Although the biomarker profile placed only 21% of
the exposed workers in a high or moderate risk
group, 87% of the bladder cancer cases in the entire
cohort were found in this group, and all of the tumors
were clinically organ-confined [40,41]. More interestingly, a positive biomarker profile occurred 15 to
33 months before the clinical detection of bladder
cancer. This study demonstrates that screening a high
risk population using biomarkers may offer an early
detection advantage. If early diagnosis translates into
detection of tumors prior to progression, clinicians
may be able to manage bladder cancer patients with
bladder preservation treatments and prolong the time
to cystectomy. Parekattil et al. have developed a neural network using urine levels of nuclear matrix protein-22, monocyte chemoattractant protein-1, and
urinary intercellular adhesion molecule-1 to identify
patients with bladder cancer. This algorithm has
100% sensitivity and 75% specificity for identifying
patients who will require cystoscopy, patients who
have bladder cancer, and patients who have muscleinvasive disease. Interestingly, they suggest that
screening of potential bladder cancer patients with
this neural network may save 41% of the cost of conventional bladder cancer diagnosis [42].
AND
BLADDER CANCER
Individuals with bladder cancer are at significant risk
for developing another bladder tumor. Clinically,
these subsequent neoplasms are all called recurrences and a distinction is not made between second
primary tumors and growth of occult residual disease
(polyclonal vs. monoclonal). Cystoscopy is the conventional method for following these people and has
excellent sensitivity and specificity in experienced
hands. Furthermore, it enables the excision of recurrent tumors without an open surgical procedure.
However, cystoscopy has its limits and is particularly poor for detecting CIS. Furthermore, the use of
fluorescence cystoscopy strongly suggests that this
investigative technique results in more complete
tumor resection [43]. Conventional indicators of
recurrence such as grade, stage, and multicentricity
provide useful indications of the risks of recurrence
in a population at risk but have poor predictive value
on an individual basis [44].
Biomarkers can improve the surveillance of patients
with recurrent bladder cancer who are currently
being assessed by periodic cystoscopy by improving
the detection of occult or missed disease or identifying patients who, despite abnormal appearing urothelium, do not have bladder cancer. Tests with high
specificity and high positive predictive value will be
most useful for indicating the need for random biopsies when no disease is seen. Tests with high sensitivity and high negative predictive value are useful
for avoiding biopsies and perhaps decreasing the frequency of cystoscopic surveillance. Currently, the
test with greatest specificity for the detection of
occult CIS is urine cytology [45]. However, urine
cytology is not an easy test to perform and is associated with significant variability. Soluble urinary
markers for bladder cancer have a lower specificity
71
and are not indicators for random biopsy [46]. A fluorescence in situ hybridization (FISH) assay
(UroVysion) demonstrates increased risk for tumor
recurrence when it is positive and the cystoscopy is
negative [47]. However, the clinical utility of this
observation appears low because most patients will
still be free of detectable tumor 1 year later. The
alternative use of markers uses the high negative predictive value of tests with high sensitivity. When the
UroVysion assay and cystoscopy are negative, the
risk of recurrence is very low in the ensuing 6
months. Other markers also have high negative predictive value. For example, the combination of cytology and DD23 has a negative predictive value of
90% [48]. Although evidence is meager, the current
data suggest that many of the currently available
markers could be used to clarify the meaning of an
abnormal appearing bladder and would be more
informative when they are negative than when they
are positive.
could be maintained on the conventional surveillance schedule. The second risk is related to time.
Even low to moderate grade tumors can eventually
cause problems and require cystectomy. For this reason, a biomarker based follow-up strategy is not
meant to replace but to decrease the frequency of
cystoscopy. The periodicity of this fail-safe cystoscopy needs to be determined and validated in a
prospective study, but presumably would be between
6 and 12 months. While the existing data and retrospective analyses suggest that this approach is reasonable and cost- effective, safety (the risks of
metastasis and cystectomy) cannot be effectively
modeled. A prospective study is needed and is likely
to validate this approach and usher in a new era for
the surveillance of bladder cancer.
Summary
Currently available biomarkers have good sensitivity, particularly for high grade bladder cancer,
and moderate to good specificity. The general use
of these markers focuses on positive predictive
value, which in a group of individuals at high risk
for recurrence is moderate to good. A second but
often neglected use of biomarkers takes advantage of their negative predictive value. Several of
the currently available biomarkers have high
negative predictive values and could be used to
prolong the cystoscopic interval, particularly in
patients with low-risk bladder cancer. A prospective trial is needed to determine the cost savings,
change in quality of life, and safety of this strategy.
Surveillance for recurrent bladder cancer is performed using an arbitrary schedule. Conceivably,
validated biomarkers could be used to individualize
the cystoscopic interval based on periodic noninvasive testing. There are obvious benefits and risks to
this use of biomarkers. The benefits include fewer
invasive procedures (cystoscopy with or without
biopsy) and less expense. Retrospective data suggest
that this can be accomplished [49]. However, this use
of biomarkers also has some risk, and the risk is not
based on a normal distribution. The risk to the individual being followed by a biomarker-based strategy
is asymptotic. The greatest risk would be missing a
high grade tumor that could metastasize and be fatal.
A risk with significant but lower impact on the
patient would be missing a superficial tumor that
would progress but be cured with cystectomy. A third
and lower risk is missing small superficial tumors
that could be treated in the office setting by fulguration but now require transurethral resection in the
operating room. An obvious concern is low probability that any biomarker will always exhibit 100% sensitivity. Nevertheless, this approach of providing
individualized surveillance appears feasible. The risk
of a serious adverse event (death from bladder cancer or need for cystectomy) is related to tumor biology and time to surveillance. It is important to recall
that even with regular scheduled surveillance these
events still occur. Fortunately, biomarkers have their
greatest sensitivity for high grade tumors. If this did
not provide enough reassurance of the limited risk
with this approach, patients with grade 3 tumors
III. IDEAL TUMOR MARKER
Several criteria have been established to assess the
usefulness of a substance as a marker for the diagnosis and surveillance of cancer. The attributes of an
ideal tumor marker include technical ease of assaying, low intra-assay and interassay variability, and
high accuracy [6,50]. In this section, we will discuss
the attributes of an ideal tumor marker by considering the development of a hypothetical bladder tumor
marker, MDVL. Consider that MDVL is a secreted
protein synthesized by normal urothelial cells; however, its expression is fourfold to eightfold elevated
in bladder tumor cells. Two highly specific monoclonal antibodies are available for MDVL and, using
these antibodies, MDVL can be detected in the cul-
72
ture-conditioned media of bladder cancer cells, bladder tumor tissues, and urine specimens. MDVL transcripts can also be detected in tumor cells and exfoliated cells by real time-polymerase chain reaction
(RT-PCR) analysis. In the following paragraphs, we
will discuss how one can evaluate whether MDVL is
a useful bladder tumor marker, and whether it can be
developed into a clinically applicable diagnostic test.
DNA alterations, Quanticyt nuclear karyometry, and
DD23 marker are either ELISAs, RT-PCR, or microscopic image analysis and require that urine specimens be sent to a central laboratory for assay. In the
case of our hypothetical marker MDVL, a qualitative
point-of-care sandwich dip-test, a quantitative
ELISA, and an RT-PCR assay can be developed.
1. TECHNICAL SIMPLICITY OF DETECTION
Accuracy of a marker or diagnostic test is influenced
by how much variation the test or marker displays
during testing. The variation may result from specimen stability, conditions of specimen storage, or
variation and shelf life of test reagents. For any bladder tumor marker, including our hypothetical marker
MDVL, variability can be calculated by determining
the intraclass and interclass correlations. The intraclass correlation can be evaluated by assaying the
marker in the same specimen at multiple times in a
single experiment, followed by computing one-way
analysis of variance. If the intraclass correlation
approaches 1.0, it indicates that the assay has low
intra-assay variability. For calculating the interclass
variability, the marker can be assayed using the same
sample but in different experiments. Pearson’s correlation analysis is performed on test results; if the
Pearson’s r approaches 1.0, it indicates that the
marker has low variability.
2. RELIABILITY
Since cystoscopy is invasive and patients consider it
uncomfortable, the main argument for designing a
bladder tumor marker is that it be noninvasive. Of
possibly greater importance, given our increasing
understanding of the molecular aspects of bladder
cancer, is the possibility of identifying markers that
might be used to characterize and predict the biological potential of a particular diathesis. It is relatively
easy to design a bladder cancer test, since many
“molecular determinants” of bladder tumor growth
and invasion are released into urine when it comes in
contact with the tumor during storage in the bladder.
Thus, many bladder cancer tests, such as BTAStat/TRAK, UBC-Rapid, UBC-IRMA, BLCA-4,
HA-HAase, NMP-22, and survivin detect soluble
markers released in urine (product inserts of BTAStat/TRAK, NMP-22, UBC) [51,52]. In addition,
tests such as UroVysion (multicolor FISH), uCyt+,
microsatellite DNA analysis, telomerase, DD23, etc.,
detect either genetic alterations or cell-surface antigens that may indicate biologic characteristics of a
particular cancer. These tests require exfoliated
tumor cells in voided urine specimens or in bladder
wash specimens as the starting material [6,48,51,52].
Since our hypothetical bladder tumor marker MDVL
is secreted in urine, a urine-based sandwich ELISA
(enzyme-linked immunosorbent assay) can be developed using the 2 monoclonal antibodies to detect
levels of MDVL protein. In addition, an RT-PCR
assay can be developed to detect the expression of
MDVL transcript in exfoliated cells for diagnosing
bladder cancer.
3. STATISTICAL PARAMETERS FOR EVALUATING
MARKER EFFICIENCY
a) Contingency Table
Accuracy and reliability are the most critical parameters that determine the usefulness of a marker in
diagnosing bladder cancer. This is because a false
positive result leaves patients with unnecessary anxiety and the prospect of further costly and invasive
testing. Contrarily, a false negative result provides
patients a false sense of security and exposes them to
the risk that their disease may progress and not be
detected, resulting in a poorer prognosis. Since we
must apply statistical measures for assessing the usefulness of markers, it may be useful for the reader to
define some of the terminologies that are applied.
The efficacy of a bladder cancer marker is analyzed
by testing it in both populations with and without
bladder cancer. The test inferences are then analyzed
using a “2 x 2” contingency analysis. For example,
we can measure MDVL concentrations in urine specimens from 200 individuals. Among these, 100 are
patients with bladder cancer and 100 are control individuals either with other conditions that may produce
A point-of-care assay for the measurement of bladder
cancer is desirable, since the diagnosis can be made
immediately in a physician’s office. Of the various
tests designed for detecting bladder cancer, hematuria detection, BTA-Stat, NMP-22 (point-of-care
test), and UBC-Rapid are dipstick tests and can be
performed in the urologist’s office. Other tests such
as BTA-TRAK, NMP-22 (original), telomerase
(TRAP assay and hTERT RT-PCR), uCyt+,
UroVysion, HA-HAase, BLCA-4, microsatellite
73
falsely positive assay results (see below) or with no
clinical problems. When the MDVL test is performed, the test inferences will fall into 1 of the 4
compartments of the contingency table. True positives (TP) will be positive MDVL results in those
individuals who have bladder cancer. False negatives
(FN) will be negative MDVL results in those individuals who have bladder cancer. Correspondingly,
true negatives (TN) will be negative MDVL results
in those individuals who do not have bladder cancer,
while false positives (FP) will be positive MDVL
results in those individuals who do not have bladder
cancer. Based on these 4 populations, one can determine the sensitivity, specificity, accuracy, positive
predictive value, and negative predictive value of the
marker. These contingency tables are used to evaluate the statistical significance in cross-sectional, retrospective, and prospective studies.
invasive urine test as a standard mode of surveillance
if the test has a more than 10% false negative rate
[66]. Therefore, for our hypothetical marker MDVL
to become clinically useful, in terms of the sensitivity issue, it will have to be tested in multi-center trials and in heterogeneous community settings that
include bladder cancer patients with primary and
recurrent bladder cancers of different grades and
stages.
c) Specificity
Specificity is equally as important as sensitivity
when evaluating the usefulness of a marker. Specificity is defined as the percentage of individuals
without the disease in whom the test is negative, and
is calculated as TN/(TN + FP) x 100. The false positive rate is the reverse of specificity, and is calculated as FP/(TN + FP) x 100. For the ideal tumor marker, the specificity and false positive rates should
approach 100% and 0%, respectively. As is the case
for sensitivity, specificity of a marker depends on the
composition of the study population. For example,
many bladder cancer markers have greater than 90%
specificity among healthy individuals, but have low
specificity among patients with hematuria or lower
urinary tract infection and inflammation. For example, specificities of BTA-Stat/TRAK and NMP-22
tests vary depending upon the degree of hematuria
and inflammatory conditions [67-69, BTAStat/TRAK product inserts]. Knowledge of conditions other than bladder cancer that may cause a positive result may reduce anxiety and eliminate the
need for further assessment. In evaluating the specificity of our hypothetical marker MDVL, the control
population should include patients with a variety of
benign urologic conditions.
b) Sensitivity
In our example, the sensitivity of the MDVL marker
is defined as the percentage of bladder cancer
patients in whom the test is positive. It is calculated
from the contingency table as TP/(TP + FN) x 100.
The false negative rate is just the opposite; it is calculated as FN/(TP + FN) x 100. For an ideal tumor
marker, the sensitivity and false negative rate should
approach 100% and 0%, respectively. Low sensitivity (higher false negative rate) of a marker may
increase the risk for bladder cancer progression due
to missed diagnosis [1,6,51]. However, it is important to understand that the sensitivity of a marker
depends upon the population in which it is evaluated
[53]. For example, the hypothetical marker MDVL
may show 90% sensitivity to detect large high grade
and advanced tumors, but show less sensitivity to
detect low grade and recurrent tumors, which usually are smaller in size [46,53]. This may be the case
for many urine-based markers since a large volume
bladder tumor would ensure the secretion of large
concentrations of different markers or the shedding
of large numbers of tumor cells into the urine. In this
regard, several markers (BTA-Stat/TRAK, NMP-22,
UBC, telomerase (TRAP assay), microsatellite DNA
analysis, UroVysion, and uCyt+) have been found
to have lower sensitivity to detect low grade and low
stage tumors when compared to high grade, high
stage tumors [46,55-65]. In addition, several tumor
markers have lower sensitivities for detecting recurrent tumors than primary tumors because of the
smaller size of recurrent tumors [54,55]. Interestingly, patients with bladder cancer appear to be reluctant
to switch from cystoscopy to relying solely on a non-
d) Deciding Cutoff Limits for Sensitivity and Specificity Determinations (ROC Curve)
When a diagnostic test involves quantitative measurement of a particular marker, a cutoff limit is set
to distinguish between positive and negative inferences. If the cutoff limit is set too high, the marker
will be very specific, but the sensitivity will
decrease. Conversely, if the cutoff limit is set too
low, the marker will have high sensitivity, but the
specificity will suffer due to increased false positive
cases. For example, the sensitivity of BTA-TRAK
varies between 58% and 77% at a threshold level of
14 U/mL, which is the cutoff limit recommended by
the manufacturer. The specificity of the test at this
threshold level varies between 54% and 75% [7072]. However, at a cutoff limit of 1300 U/mL, the
specificity of the test increases to 95%, but its sensi-
74
even if a marker has the same sensitivity and specificity in those different populations [6,53]. Therefore, extrapolating the PPV and NPV obtained in a
study population and applying them to the general
population is not only incorrect, but may prove to be
costly, misleading, and, therefore, not without risk.
tivity decreases to 13% [29]. Similarly, the sensitivity and specificity of the NMP-22 test vary in different studies, which may be a reflection of the various
thresholds used in these studies (3.6 U/mL-12 U/mL)
[6,51].
Choosing the correct cutoff limit depends upon the
type of population in which the marker will be tested. This is determined by generating a receiver operating characteristic (ROC) curve. To generate an
ROC curve, the sensitivity and specificity values of
a test or marker at different cutoff limits are calculated. The ROC curve is plotted as sensitivity versus
specificity. If a marker is to be used for monitoring
recurrence, the cutoff limit may be set at the lower
end, such that the marker has high sensitivity and
reasonable specificity. If a bladder cancer marker is
used for screening, the cutoff limit could be set at the
higher end, such that the number of false positive
cases is decreased. Since the prevalence of bladder
cancer in the general population is low, this is the
approach that has been applied as a corollary. For the
hypothetical marker MDVL, urinary levels are measured using an ELISA, and therefore, an ROC curve
can be generated to determine the cutoff limit. There
will be a trade-off between sensitivity and specificity, depending upon whether MDVL is to be used for
monitoring bladder cancer recurrence or for screening a high-risk population for cancer.
In the following examples, we illustrate this concept
using our hypothetical marker MDVL. In the first
example, MDVL has 85% sensitivity and 85% specificity to detect bladder cancer and is being tested in
a study population of 1000 individuals. In this scenario, the 1000 individuals are part of a communitybased screening program. The SEER/NCI (Surveillance, Epidemiology, and End Results/National Cancer Institute) database indicates that the prevalence
of bladder cancer in the general population is 0.1%
[19]. Assuming a prevalence of 0.1% in our study
population, the PPV and NPV of MDVL will be
0.56% and 99.99%, respectively. This means that
less than 1% of individuals who test positive on
MDVL will have bladder cancer.
In the second example, let us consider a population
of 1000 individuals who are 65 years or older. Twothirds of bladder cancer cases occur above the age of
65 years [73,74]. Britton et al. and Messing et al.,
when screening a general population for hematuria,
found that the prevalence of bladder cancer among
individuals above the age of 50 or 60 years is higher,
about 0.7% [20,27]. Thus, considering a 0.7% prevalence of bladder cancer in this group of individuals,
the PPV and NPV of MDVL will be 4% and 99.9%,
respectively. These examples demonstrate that
screening the general population for bladder cancer
in the real world will be costly, regardless of a marker’s sensitivity.
e) Accuracy
Accuracy of a tumor marker or test is a function of
both sensitivity and specificity. It is expressed as a
percentage and calculated as (TP + TN)/total number
of study individuals X 100. Since both sensitivity
and specificity are valid only for the population in
which the marker is tested, accuracy of a marker is
also dependent on the study population and the cutoff limit used for calculating the sensitivity and
specificity of the marker.
The risk of bladder cancer among smokers, painters,
and industry workers exposed to arylamines is threeto sixfold higher than it is in unexposed individuals
[29,31,34,75-78]. The risk is even higher if smoking
or occupational exposure to bladder carcinogens is
combined with other risk factors, including genetic
polymorphism [29,75,77,79,80]. For example, in a
case-control study, smokers with polymorphisms in
glutathione S-transferase (GST) M1 and T1 genes
(GST M1- or GST T1-null phenotypes) were found
to have about a threefold increased risk of bladder
cancer when compared to controls or smokers with
wild type genes [81]. Similarly, in a case control
study, heavy smokers were found to have a sevenfold
increased risk of bladder cancer if they also had
polymorphisms in folate metabolic genes, such as
methylene-tetrahydrofolate reductase (MTHFR)-TT
or CT phenotypes or methionine synthase (2756 A-
f) Positive and Negative Predictive Values
The other 2 terms that are often used for evaluating
the usefulness of a marker are positive predictive
value (PPV) and negative predictive value (NPV).
Both PPV and NPV are dependent on the prevalence
of the disease in a study population. PPV is defined
as the percent of individuals in whom the test or
marker is positive and the disease is present. It is calculated as TP/(TP + FP) x 100. NPV is defined as the
percent of individuals in whom the test is negative
and the disease is not present. NPV is calculated as
TN/(TN + FN) x 100. Since PPV and NPV depend
upon disease prevalence in a population, these values
can be either high or low in different populations,
75
4. BIOCHEMICAL MARKERS AND
MA OF EARLY DETECTION
G) phenotype [82]. Among permanent hair dye users,
the risk of bladder cancer is increased threefold if
they have N-acetyltransferase 2 slow acetylator phenotype [83]. In a study by Hemstreet et al., the total
incidence of bladder cancer among a moderate to
high-risk group of Chinese workers exposed to benzidine (as defined by the biomarker profile) was
fourfold higher than that in the entire cohort of workers who were either exposed or unexposed to benzidine [40]. Assuming a 4.5% prevalence due to
increased risk, the hypothetical marker MDVL, with
85% sensitivity and 85% specificity, would have
21.1% PPV and 95.5% NPV.
THE
DILEM-
Currently, cystoscopy is the gold standard for detecting bladder cancer, with urine cytology serving as a
useful adjunct for high grade disease. Cystoscopy
visualizes the tumor mass. Urine cytology evaluates
malignancy based on cellular and nuclear morphology. In contrast, various noninvasive biochemical and
molecular markers can detect tumor-associated
molecules in the nano- or picomolar range (e.g.,
ELISAs, dipstick tests) or can identify a single
abnormal cell (e.g., immunocytochemistry, RT-PCR,
and FISH). Therefore, many of these markers could
conceivably detect bladder tumors before they were
clinically documented. Such “false positive” results
would create a dilemma for urologists: should they
offer treatment that might produce side effects or
wait until the tumor becomes cystoscopically visible,
when it may have progressed in grade or stage
[6,51]?
An interesting comparison is that of PSA screening
and prostate cancer detection. In various screening
studies, regardless of whether total PSA or free PSA
to total PSA ratio is used to detect prostate cancer,
the PPV of PSA varies between 17% and 36%
(assuming an incidence of about 3%) [84-86].
Widespread acceptance of PSA screening for
prostate cancer has been based on the suggestions
that screening for prostate cancer is medically beneficial and economically feasible. However, this
assumption has not been without controversy. The
controversy is centered on the basic premise that elevated PSA does not actually reflect the presence of
cancer and that the diagnosis of clinically nonsignificant prostate cancer is costly economically, as well
as emotionally and psychologically devastating.
Therefore, implementation of a screening program
for bladder cancer would require general acceptance
of a particular marker (or panel of markers) by both
urologists and their patients in a global sense.
The significance of false positive results in identifying the presence of a bladder tumor within a specified time can be evaluated by calculating risk ratio
and odds ratio (OR). For example, Hemstreet et al.
suggested that the risk of developing bladder cancer
among biomarker positive individuals was high, with
the risk ratio for various markers ranging between 16
and 38 and the OR ranging between 40 and 46 [40].
The biomarker profile in this study predicted the
presence of bladder cancer 15 to 33 months before
actual clinical detection of the disease. In another
study, where a cohort of 70 patients was followed for
bladder tumor recurrence over a period of 4 years,
the HA-HAase test had 91% sensitivity, 70% specificity, 87% accuracy, 92% PPV, and 67% NPV to
detect recurrence. Interestingly, out of the 14 false
positive cases, 6 recurred within 5 months, whereas
only 4 out of the 33 true negative cases recurred during the same period. Thus, a “false positive” HAHAase test carried a 3.5-fold increased risk of tumor
recurrence within 5 months (risk ratio = 3.5). In this
study, usefulness of the HA-HAase test and the BTAStat to monitor bladder tumor recurrence was compared in a subset of 26 patients [38]. In that subset,
an apparently false positive HA-HAase test carried a
tenfold risk of recurrence (risk ratio = 10.2), whereas a false positive BTA-Stat test did not indicate a
risk of recurrence within 5 months (risk ratio = 1.4).
Similarly, in some studies, the UroVysion test has
been shown to predict recurrence. Skacel et al.
reported that 8 out of 9 FISH-positive patients with
An important objective for use of a noninvasive
marker in surveillance for bladder cancer is to
increase the interval between cystoscopic examinations without missing any tumor recurrence [46]. In
the absence of a well-accepted biomarker, bladder
cancer patients now undergo cystoscopy at scheduled intervals. A false positive test or marker inference resulting in cystoscopic examination is of lesser concern than a false negative inference that may
lead to tumor progression [87]. The prevalence of
bladder cancer among patients with a history of bladder cancer varies between 26% and 70% [7]. In the
last example, assuming the prevalence of bladder
cancer at 35%, the PPV and NPV of MDVL among
patients with a history of bladder cancer will be
75.3% and 91.3%. Thus, a noninvasive marker with
high sensitivity and reasonably good specificity may
have a place in the management of recurrent bladder
cancer.
76
atypical cytology but negative biopsy had biopsyproven bladder cancer in 12 months [88]. These
examples indicate that evaluating a marker’s performance based solely on cystoscopy observations may
be misleading and ultimately inaccurate [89].
IV. GOOD CLINICAL PRACTICE IN
MARKER DEVELOPMENT
As we begin our discussion into tumor markers for
bladder cancer, it is important to define our terminology. The search for determinants (”biomarkers”)
to better understand the biology of cancer, to
improve the detection and monitoring tumors in
patients, and to predict the outcome and response to
treatment of cancer has been the focus of much
research. Considering the relative incidence and
mortality from bladder cancer, there are an amazing
number of markers that have been explored. Part of
this relates to the unique situation found in the bladder and the many bodily fluids that are accessible for
analyzing bladder markers. These materials include
urine, serum, and cytologic cells, as well as biopsy
samples.
An accurate knowledge of genitourinary conditions
that may cause false positive results in a biomarker
test, measuring quantitative changes in levels of a
marker rather than simply noting its presence or
absence, repeat testing, improving the clinical means
of confirming malignancy, and testing the marker in
large community settings will help clinicians decide
on the best course of action when a biomarker is positive in the absence of a visible tumor in the bladder.
Such information may complement the information
provided in assessing risk ratio and OR.
Summary
Urine is probably the most unique environment in
which to study tumor markers. The urine is an environment that very few organs have exposure to and,
therefore, identifying markers in the urine often
leads to higher specificity than those found in serum
samples. The urine is also a harsh environment for
many proteins, allowing for the subtraction of many
proteases and other types of degrading enzymes,
which often make it difficult to develop assays for
markers. While this environment is unfriendly for
many proteins, it does provide stability to those that
are able to survive in it and, therefore, allows an
opportunity to focus on this unique set of proteins. In
addition, cells are also located within the urine
allowing cytology and cytologic examination. These
cells represent unique looks into the bladder in a
noninvasive fashion. Therefore, many markers are
being developed to better examine these cells and to
determine their biologic features implicating the
propensity to act as malignant cells.
For a biomarker to be clinically useful, it should
have technical simplicity, reliability and high
accuracy (i.e., high sensitivity and specificity).
However, in addition to high sensitivity and specificity, the usefulness of a marker will depend on
the population in which it is used. If a marker is to
be used for bladder cancer screening, it should
have high specificity and high PPV in order to
avoid unnecessary anxiety and expense due to too
many false positive results. If a marker is to be
used for monitoring bladder tumor recurrence, it
should have high sensitivity and high NPV in
order to detect each and every case of bladder cancer.
The physician’s dilemma related to the possible
early detection of bladder cancer by biomarkers
could be decreased by examining the risk of
developing bladder cancer in a specified time
when a biomarker is positive in the context of
other conditions which may result in a false positive biomarker test.
The serum is an environment that has not been wellexplored in bladder cancer, mainly because of the
fact that urine has been an easier environment in
which to study unique changes that may be associated with the bladder. There are some markers that are
being identified in the serum of individuals with
bladder cancer, but these are typically markers of
advanced or metastatic disease.
The overall acceptance of a noninvasive test for
bladder cancer in clinical decision-making would
not only depend upon its performance, but also on
physician and patient willingness to accept its
usefulness.
77
Unfortunately, the results of such biomarker studies
are often inconsistent and sometimes contradictory.
Recognized problems include different methods of
performing assays, the use of different subsets of
patients (difference in stage or treatment) and endpoints (e.g. local vs. distant recurrence vs. survival),
and inadequate study design, leading to incompatible
data sets. This has impeded understanding the role of
new markers. Since replication and independent confirmation are hallmarks of the scientific method, the
implementation of standards and conventions is
essential for the comparison and integration of studies conducted at different institutions and different
times.
and studies: for example, sample size considerations
[91,92], requirements for validation of prognostic
models [93], and comparison of classification systems in terms of prognostic value. [94] In addition,
Simon and Altman and others have suggested methods of classifying the stages or phases of tumor
marker development [95-99]. Drew and colleagues
extended the list of goals to include a fourth type of
study in marker development, which aims to evaluate treatment effects on subsets of patients identified
by a marker or factor [99]. Not emphasized in these
recommendations and classifications is the prerequisite and fundamental requirement of assay validation.
As you will read in this chapter, the work on tumor
markers in general but, specifically, those in bladder
cancer that will be discussed here, is often made difficult to discern based upon the fact that there is no
common terminology in place for authors to describe
where their work really stands and where given
biomarkers are in their developmental phases. This
has made it often difficult for clinicians to interpret
whether a marker is ready to be used in the clinic or
still needs much additional investigation.
2. PHASES OF MARKER STUDIES
Although there has been discussion for establishing
general methodological principles and guidelines for
design, conduct, analysis, and reporting of marker
studies (analogous to those for clinical trials), these
have not been widely implemented, and there are no
well-recognized prototypes or models that can be
used to design marker studies. Those studying bladder cancer, because of many of its properties as
described above, have really been quite fortunate in
that a number of leading scientists from a wide range
of disciplines have chosen to focus on this disease as
a template for development of biomarkers to
improve the diagnosis, prevention, and treatment of
this disease. As a result, 4 phases can be defined
through which markers are developed:
1. AIMS OF MARKER STUDIES
In establishing the utility of a marker for clinical use,
investigators must demonstrate that (a) the marker
can be reliably and consistently measured, (b) the
marker has good sensitivity and specificity so it can,
with reasonably high probability, identify patients
with a better or worse prognosis or with a greater or
lesser likelihood of having a specified condition, and
(c) the use of the marker will improve outcome by
targeting therapeutic or diagnostic interventions. It
should also be emphasized that the development and
understanding of new tumor markers is best accomplished as part of a clinical and biological model
with study designs that reflect the underlying mechanisms of cancer development and/or progression,
including knowledge of specific pathways.
a) Phase I: Assay Development and Evaluation of
Clinical Prevalence (Feasibility Studies)
A reproducible and optimized assay is the essential
prerequisite prior to the application to clinical samples. This should be complemented with feasibility
studies documenting the prevalence and expression
of the markers of interest and examining their association with demographic and clinical characteristics
in a representative study cohort (target population).
b) Phase II: Evaluation Studies for Clinical Utility
As in the setting of clinical trials research, there is a
need to standardize different phases of tumor marker
development, and to develop general guidelines and
protocols for broadly accepted (or at least understood) principles of conducting and reporting translational marker studies.
These studies may include the further optimization
of the assay methods and/or interpretation of the
assay results, to address a defined logistic/practical
issue. The ultimate goal of this phase of investigation
is to refine hypotheses and to define standards that
can be used to perform the Phase III studies. It is
essential that the results of Phase II studies translate
into standards and criteria that can be used by other
investigators.
To address the absence of standards, Altman et al.
proposed a series of guidelines for validation/confirmatory marker studies. [90] Points discussed by Altman were extended and discussed in separate articles
78
c) Phase III: Confirmation Studies
tein-based
including
immunohistochemistry,
immunoblotting, and other techniques. Alternatively,
DNA-based or nucleic acid-based approaches can be
used. Unfortunately, many investigations of potential
markers do not exceed this phase and therefore are
not developed into clinical assays.
Phase II findings are replicated, and hypotheses generated previously are tested with sufficient power in
a larger defined clinical setting in an independent,
prospective cohort of patients. The clinical utility of
a given marker assay, its performance, and interpretation is established in that phase.
The phase II of assay development is the step in
which the biomarker typically moves from the individual research laboratory to a more clinically related laboratory that has more expertise related to clinical assays. The primary goal of this phase of development is to determine important characteristics of
the assay. The first is referred to as the sensitivity or
the true positive rate. This is the indication related to
the number of, for example, bladder cancer cases that
the assay is able to detect. If it is able to detect 100%
of the cases, then the sensitivity or the true positive
rate is 100%. In addition to the true positive rate, at
this phase the false positive rate, the specificity of
the assay, is analyzed. This helps to estimate how
many individuals without bladder cancer are actually being detected positive with the given marker.
Finally, if the assay allows, an ROC curve for the
marker should be performed. These curves allow for
identification of both the true sensitivity and specificity of the assay.
d) Phase IV: Validation and Technology Transfer
as Application Studies
The aims of Phase IV studies are (a) to transfer the
techniques and established methods of the assays and
other aspects of the technology and (b) to evaluate
the ability of other investigators and clinicians at
other institutions to apply these methods and interpret the results. The Phase IV study is the final step
in the translational research process, in which a
given biomarker is incorporated into clinical practice.
3. IMPLEMENTATION
DEVELOPMENT
OF
PHASES
OF
MARKER
Often with Phase I and Phase II studies, there are single institutions with resources to perform these
investigations. However, a multi-institutional approach offers many advantages even in these initial
phases. Adequately sized and representative samples
of patients may be easier to achieve in a large collaborative network with sufficient numbers of specimens to define and select the most appropriate set of
samples. In addition, identifying sources of variability during these phases of biomarker development is
required for correctly designing the next Phase III
study and for confirming the conclusions reached in
this evaluation phase.
For the successful completion of Phase III and Phase
IV studies of marker development, it is most likely
that in the future only an international multi-institutional network will be able to perform this last
required step. These phases aim to provide insight to
understand the interrelationships between a given
marker and the intrinsic prognosis for a patient, the
effects of treatment, and effects on quality of life. As
a result, these studies become more complex and
require both larger numbers of patients and a sufficiently heterogeneous, yet representative, sample of
patients. Furthermore, markers are often most useful
in a well-defined subset of patients, and even large
single center studies may have insufficient statistical
power to detect these effects in the subset. Finally,
since independent data sets are needed for all validation studies, accruing new patients or collaborating
with other groups can only accomplish these later
phase studies. The establishment of a collaborative
network would clearly facilitate these essential interactions.
With this fertile environment for developing tumor
markers, many markers have been analyzed for
Phase I. Typically, these first analyses involve the
comparison of alterations in tumor tissue to normal
adjacent tissue and/or to normal controls. However,
it has to be of note that field effects are an established
integral part of the development of bladder cancer,
which warrants not only to include “normal” adjacent tissue but also tissue and samples from healthy
individuals as important controls during this early
phase of studies. Often at this stage, the test is pro-
79
Summary
that is, the likelihood that the method can identify the
absence or presence of a bladder neoplasm. The positive and negative predictive values of a voided urine
interpretation can also be calculated and are probably
more important to patient care. Considering that
urine cytology is used primarily to stimulate additional studies and sometimes to alter topical therapy
and that other methods of detection are available, the
reliability of an interpretation is arguably more
important than the total number of cases identified.
In this regard, cytology has a favorable record, at
least for aggressive carcinomas, with false positive
and false negative results being very few.
As you will see from this chapter, there are many
markers that are in various phases of development
for bladder cancer. With this in mind, there are
now a number of exciting markers that are at different stages of development and are moving into
clinical utility. In addition, consensus of general
methodological principles and guidelines for design, conduct, analysis, and reporting of marker studies is warranted and can be achieved. This will
enhance the development of more effective therapy and foster the integration of new tools and strategies that will help standardize their use in pathological and clinical applications.
Voided urine cytology has a high specificity - that is,
the method is good at determining the absence of a
bladder tumor and false positive interpretations are
unusual [100-105]. Values for specificity approach
100% in many studies. The method is not as good for
detecting the presence of a neoplasm, where the false
negative rate is higher. A wide range of figures have
appeared in the literature but most reports have
recorded sensitivities in the range of 35% to 65%.
Urine cytology is especially valuable for differentiating high grade urothelial carcinomas from low grade
urothelial neoplasms, a feat that “markers” have not
yet achieved. Even in studies where the adequacy of
sampling has not been addressed, high grade carcinomas have been detected with sensitivities and positive predictive values in the range of 80% to 90% of
cases [100-102,106,107]. This is especially important when the patient’s neoplasm is progressing from
low to high grade. In contrast, low grade neoplasms
are not readily identified using voided urine cytology [52,101,102,106,108,109]. Sensitivities in the
range of 20% are commonly recorded, and few studies have documented figures higher than 60%. The
difficulty in pathologic recognition of the disaggregated cells of low grade urothelial neoplasms is
almost certainly due to the absence of anaplastic
changes in these tumors. Very few low grade urothelial neoplasms are malignant and their cells reflect
this fact. One might even contend that a “positive”
cytology result rendered on cells emanating from a
papillary urothelial neoplasm of low malignant
potential (G1) is an interpretive error and that “negative,” or perhaps “reactive,” is a more accurate
diagnosis.
V. URINE CYTOLOGY: THE
STANDARD NONINVASIVE
BLADDER TUMOR MARKER
The most efficacious approach to the detection of a
bladder neoplasm is to identify the tumor cells themselves. At present, the only well-established way to
achieve this goal is through consultation with a
pathologist, asked to interpret tissue specimens or
urinary samples. The pathologic interpretation of urinary samples is included in the discussion of markers both for comparison and completeness, but it is
essential to emphasize that “urine cytology” is not a
laboratory test and that the entities being detected
using this method are not markers of a tumor, but the
cellular components of the tumor itself.
Pathologic assessment of a randomly voided urine
specimen is the standard noninvasive method in current use. Often called simply “urine cytology,” this
approach is used primarily to monitor patients with a
history of “bladder cancer” for the detection of new
urothelial tumors. These new bladder neoplasms are
traditionally called “recurrences” but they are usually not at the same site as the index lesion and may
not be the same grade or stage as the initial lesion.
Urine cytology requires no patient preparation, inexpensive equipment, and very little time. It does
require trained preparatory personnel and pathologists who can maintain their expertise through examination of large numbers of specimens and who are
willing to render unequivocal judgments.
Whatever the indicator of success, the results of
urine cytology must be understood in light of two
important factors of bladder cancer: sampling error
and tumor load. Neither random voided urines, nor
bladder washings for that matter, contain tumor cells
The clinical value of voided urine cytology is usually assessed in terms of specificity and sensitivity,
80
in each and every specimen, even when tumors are
present in the bladder. In at least one study, 23% of
washings obtained from patients with biopsy-proven,
high grade urothelial carcinomas in their bladders
contained no tumor cells [110]. Most data document
a 20% decrease in diagnostic yield for voided urines
compared to bladder washings [105,107]. Thus, a
negative urine cytology result cannot necessarily be
construed as a deficiency in the method when compared to other approaches. Further, urothelial neoplasms may be so small that they cannot be detected
by either cystoscopy or selected site biopsies. Many
instances of a positive urine cytology that required
months for histologic correlation have been recorded
[108,111]. Therefore, a positive cytology that is not
associated with an immediate cystoscopic or histologic correlation cannot necessarily be considered an
interpretive error.
specificity of urine cytology are very high for
potentially aggressive urothelial neoplasms, those
with the ability to invade and metastasize. The
sensitivity and specificity of urine cytology are
low for urothelial neoplasms that lack the ability
to disseminate, primarily because these tumors are
not malignant and should not be included among
neoplasms labeled “bladder cancer.”
VI. BLADDER TUMOR MARKERS
FOR DIAGNOSIS AND
MONITORING RECURRENCE
In the following section, we discuss various bladder
cancer markers and tests that are commercially available, or have shown potential to be clinically useful.
Table 1 lists all of these tests and markers. The tumor
makers are divided into 2 categories, soluble urine
markers and cell-associated markers, depending
upon whether urine specimens or exfoliated cells in
urine are used in the assay.
The cytologic features of urothelial neoplasms have
been described and illustrated by many authors in
numerous publications and are well known to nearly
all cytopathologists who are responsible for interpreting urinary specimens [112-118]. As with other
medical fields, differences of opinion for any particular specimen might occur but concentrating on education as a means to increase the sensitivity of the
method is unlikely to be any more productive in the
future than it has been in the past. More success
might be achieved by recognizing the role of urine
cytology in the initial detection and monitoring of
those urothelial neoplasms that are commonly called
“bladder cancer.”
1. SOLUBLE URINE MARKERS
a) Hematuria Detection
1. INTRODUCTION
Microscopic hematuria is common among asymptomatic adults. In community screening studies, 14%
to 22% of men age 50 years and older have hematuria and approximately 33% to 57% of the hematuria positive individuals have progressive urologic
diseases that require immediate medical attention
[20-27]. The most common finding among individuals presenting with urinary tract malignancies is
hematuria, seen in about 85% of bladder cancer
patients and 40% of renal carcinoma patients [117].
In a case-control study involving the follow-up of
1046 patients with a physician’s diagnosis of asymptomatic hematuria, Friedman et al. found that hematuria may be present in a higher proportion of cases
than controls, 5 to 6 years before the clinical diagnosis of urothelial malignancy [118]. Hematuria due to
urothelial cancers is intermittent, may be grossly visible or only visible on microscopic examination, and
is independent of tumor grade and stage [23,117].
Summary
“Urine cytology” is not a laboratory test; it is the
interpretation (opinion) of a pathologist concerning the nature of cells disaggregated from their
environment in the urothelium. Urinary specimens
do not always contain a representative sample
of the bladder and may not contain tumor cells
even when a tumor is present. Urinary specimens
may contain tumor cells when the tumor load is
too small for recognition by other methods. Voided urines usually contain fewer and less wellpreserved cells than bladder washings. The diagnostic yield of urine cytology is increased if at
least 3 samples are obtained. The diagnostic yield
of urine cytology depends upon many factors in
addition to the acumen of the pathologist. Since
the endpoint of urine cytology is to identify the
tumor cells themselves, the predictive value of a
positive result is very high. The sensitivity and
Several community-screening studies have been
conducted to test the usefulness of hematuria screen-
81
82
Table 1. Current Bladder Tumor Markers for Detection and Surveillance
83
Table 1. Current Bladder Tumor Markers for Detection and Surveillance (Continued)
84
Table 1. Current Bladder Tumor Markers for Detection and Surveillance (Continued)
ing for detecting bladder cancer in the general population. As discussed in the Tumor Markers and
Screening section, Messing et al. and Britton et al.
showed that although the prevalence of bladder cancer among men over the age of 49 years is about
0.7%, the prevalence of bladder cancer among individuals with asymptomatic microhematuria varies
between 3% and 18% [20,21,24,27]. Consistent with
the intermittent nature of hematuria, Messing et al.
have shown the benefits of repeat hematuria testing
after a 9-month interval among men over the age of
50 to detect urologic malignancies (i.e., cancers of
the bladder, kidney, and prostate) [24]. Wakui and
Shigai conducted a prospective screening study
involving a 3-year follow-up of 21 372 adults being
tested for hematuria [117]. Of the 912 individuals
who were positive for hematuria, 1 case of bladder
cancer was detected [117]. In a prospective cohort
study, Murakami et al. discovered 24 cases of urinary
tract cancers among 1034 individuals positive for
microhematuria and 4 more cases within 3 years of
testing [119]. Furthermore, in this and another study,
22% of the hematuria positive individuals had significant urological diseases requiring treatment
[119,120]. Mohr et al., in a population-based study,
followed 781 residents over a 10-year period for
microhematuria and found 8 patients with urothelial
cancers and 5 with prostate cancer [121]. The reason
for the low prevalence of bladder or other urinary
tract cancers in patients with hematuria is that hematuria may arise due to inflammatory conditions, urinary tract infection, stone disease, benign prostate
hyperplasia (BPH), and many other conditions that
produce blood in the urinary tract [39, 117, 118, 121,
122].
turia, the results of this method may vary because of
a number of factors. For example, initial, total, or terminal specimens are more likely to yield positive
results than are midstream specimens [23]. RBC
detection also depends on the methods used to prepare the specimens for microscopic examinations
including whether an immediate or an old specimen
was examined, the volume of the aliquot used, the
speed and duration of centrifugation, the methods of
decanting supernatants, and the volume used to
resuspend the sediment, as well as interobserver and
intraobserver variation [23]. If the specific gravity of
urine is less than 1.008 (quite common in wellhydrated individuals), more than 96% of RBCs may
lyse prior to microscopic examination, yielding false
negative results [23].
2. METHODOLOGY
3. RESULTS
When evaluated in the general population, microscopic appearance of red blood cells (RBCs) (< 3 to
5 RBCs per high power field) may be evident in
many individuals without any underlying clinical or
pathological condition [50]. To formulate policy
statements and recommendations for the evaluation
of asymptomatic microhematuria in adults, The
American Urological Association (AUA) convened
the Best Practice Policy Panel on Asymptomatic
Microscopic Hematuria [123]. The panel recommended that the definition of microscopic hematuria
is 3 or more RBCs per high power microscopic field
in urinary sediment from 2 of 3 properly collected
urinalysis specimens.
Earlier studies have reported that hematuria detection has high sensitivity (90%-95%) for diagnosing
bladder cancer [20-27]. However, more recent studies have reported a significantly lower sensitivity for
hemoglobin
dipstick
testing
(46%-74%)
[42,58,124,125]. A likely explanation for this discrepancy is that hematuria testing was performed
repeatedly in the earlier studies, but was done only
once in the later studies. Since hematuria is intermittent in nature, repeat testing increases the sensitivity
of the hemoglobin dipstick test.
Detection of hemoglobin using a hemoglobin dipstick is another way of detecting hematuria. The
hemoglobin dipstick test is easy to use, inexpensive,
requires little training, and does not require the presence of intact RBCs. Several community studies
involving home hematuria testing have shown that
the hemoglobin dipstick test is suitable for testing in
a convenient, natural setting (by the patient in the
privacy of his or her home or in the physician’s
office), which enhances the detection of intermittently bleeding lesions [23]. The test is available over the
counter in any pharmacy and costs about 60¢ per
test. A sample is recorded as positive when any
hemoglobin is present (trace, small, moderate, or
large). Considering that hematuria screening may
also detect other serious diseases, the cost of detecting a true positive case through such screening could
be as low as $1300 [22].
To reduce unnecessary cost and morbidity associated
with further work-up, evaluation of RBC morphology by phase contrast microscopy has been suggested
[117,126]. Schramek et al. separated individuals with
asymptomatic hematuria based on RBC morphology,
Although counting of RBCs under a high power field
is the standard method to detect microscopic hema-
85
which was examined by an interference-contrast
microscope [126]. In the dysmorphic cell group (193
individuals), with a median follow-up of 42 months,
no cases of urological malignancies were found.
However, in the eumorphic/mixed cell group (123
individuals), 13 cases of urological malignancies
were found. In a prospective screening study, Wakui
and Shiigai used RBC volume distribution curves
(RDC) generated by an automated blood cell analyzer to divide 912 subjects with a positive hemoglobin
dipstick into 2 groups [117]. Group 1 consisted of 38
individuals who showed normocytic or mixed cell
patterns, which are predictors of urinary tract cancer.
Among group 1 individuals, a single case of bladder
cancer was found (1 in 38; incidence rate 2.6%).
However, no bladder cancer cases were detected in
group 2 individuals (n = 869), who showed a microcytic pattern on RDC. The microcytic pattern probably arises due to urinary tract infection or glomerular
disorders. Thus, the RDC method appears to reduce
the total work-up cost by 93.8% when compared to a
conventional setting that involves a full evaluation of
all cases of hematuria [117]. Georgopoulos et al. suggested that the assessment of erythrocyte morphology should be carried out at pH < 7.0 and at osmolarity ≥ 700 mOsmol/kg [127]. Under these conditions,
if more than 90% of cells are dysmorphic, the blood
pressure is normal, and there is no proteinuria, hematuria is most likely renoparenchymal, requiring only
routine check-ups twice a year. However, if more
than 90% of cells are eumorphic, microhematuria is
most likely post-renal and requires a full work-up
[127].
b) BTA-Stat and BTA-TRAK
Summary
3. RESULTS
Hematuria detection is a useful first-line marker
to detect urologic diseases including urologic
malignancies. Hematuria screening for detection
of bladder cancer and other urologic malignancie
shas high sensitivity but low specificity due to a
low prevalence of urologic malignancies among
patients with hematuria. Hematuria testing by
hemoglobin dipstick is reliable and superior to
microscopic examination of RBCs. Newer techniques that help to distinguish between hematuria
originating from malignancy or other
disorders/infections should help to improve specificity without changing sensitivity.
The sensitivity of the BTA-Stat test reported in several cohort and case-control studies ranges from as
low as 9.3% to as high as 89% [38,47,55,56,5860,105,124,130-135]. The sensitivity of the BTAStat test to detect low grade tumors is low, ranging
between 13% and 55%. For G2 and G3 bladder
tumors, it varies between 36% to 67% and 63% to
90%, respectively. The specificity of the BTA-Stat
test among healthy individuals is more than 90%.
However, it has low specificity (about 50%) among
patients with urinary tract infections, urinary calculi
(90% positive on BTA-Stat) [136], nephritis, renal
stones, cystitis, benign prostatic hyperplasia, hematuria, and 2+ to 3+ protein on urine dipstick
[38,67,138,139]. The reason why the BTA-Stat test
has lower specificity among patients with any one of
the several benign genitourinary conditions is that
1. INTRODUCTION
The BTA (bladder tumor antigen)-Stat and
BTA–TRAK tests detect a complement factor Hrelated protein in urine. In addition to being present
in the urine of patients with bladder cancer, this complement factor H-related protein is produced and
secreted by several bladder and renal cancer cell
lines [128,129]. The complement factor H-related
protein has an almost identical amino acid composition and function as the human complement factor H
protein [128,129]. Indeed, both monoclonal antibodies that are used in BTA-Stat and BTA-TRAK tests
also detect the complement factor H protein. The difference between BTA-Stat and BTA-TRAK tests is
that the BTA-Stat is a qualitative point-of-care test,
whereas BTA-TRAK is quantitative, requiring testing in a diagnostic laboratory.
2. METHODOLOGY
The BTA-Stat is an immunoassay performed by
placing 5 drops of urine in the sample well of the test
device and allowing it to react for exactly 5 minutes.
A visible red line in the test window indicates a positive result, while a line in the control widow indicates that the test is working correctly. BTA-TRAK
is a standard ELISA that quantitatively measures the
amounts of a complement factor H-related protein
and complement factor H in urine (BTA-TRAK
product insert). Both BTA-Stat and BTA-TRAK tests
can be purchased from Polymedco Inc., New York,
NY, and Mentor Urology.
86
the test detects both the complement factor H-related
protein and complement factor H (BTA-Stat product
insert). Complement factor H is present in human
serum at high concentrations (0.5 mg/cc), and, therefore, the BTA-Stat test might be falsely positive in
many benign conditions that cause hematuria.
Indeed, Oge et al. showed that if urine is spiked with
blood, the specificity of the BTA-Stat varies depending upon the severity of hematuria: 80% for microscopic hematuria and 24% for gross hematuria [67].
Nasuti et al. found an 84% false positive rate for
BTA-Stat among patients with symptoms of dysuria,
incontinence, and hematuria [139]. The BTA-Stat
product insert includes a list of benign conditions in
which the test should not be performed.
dantly present in blood. Considering this possibility,
the manufacturer recommends that BTA-TRAK
should be used only with information available for
the clinical evaluation of the patient and other diagnostic procedures, and that the test should not be
used as a screening test (BTA-TRAK product insert).
According to BTA product inserts, the FDA has
approved both BTA-Stat and BTA-TRAK tests for
use as aids in the management of bladder cancer in
combination with cystoscopy.
Summary
Several case-control and cohort studies have
shown that the sensitivity of BTA-Stat and BTATRAK tests varies between 9.3% and 89% and is
dependent on tumor grade, stage, and size. The
sensitivity of BTA-Stat and BTA-TRAK also
depends upon whether the tumors are primary or
recurrent. The specificity of BTA-Stat and BTATRAK is high among healthy individuals but is
low among patients with various benign genitourinary conditions.
Both cohort and case-control prospective and retrospective studies have explored the usefulness of the
BTA-Stat test as a prognostic marker. For example,
Raitanen et al. reported that bladder cancer patients
with positive BTA-Stat tests have shorter diseasefree survivals [140]. However, the same group
reported that, while 16% of the false positive cases
on the BTA-Stat had a recurrence, the majority of the
false positive cases were due to intravesical therapy
or infection [8]. Similarly, van Rhijn et al. showed
that a positive BTA-Stat test does not predict recurrence in cases with a negative cystoscopy and biopsy [56]. Lokeshwar et al. found that a false positive
BTA-Stat result does not carry any significant risk
(risk ratio = 1.4, OR = 1.5) for recurrence within 5
months [38]. Other studies have also shown that
false positive BTA-Stat inferences do not predict
bladder cancer recurrence [59,60,141].
c) NMP-22
1. INTRODUCTION
Nuclear matrix proteins (NMP) are part of the internal structural framework of the cell nuclei [145].
This non-chromatin structure supports nuclear shape,
organizes DNA, and plays an important role in DNA
replication, transcription, and gene expression
[146,147]. NMP-22 is a nuclear mitotic apparatus
that is involved in the proper distribution of chromatin to daughter cells during cellular replication
[148]. NMP-22 is present at a relatively low level in
the interphase nuclear matrix. However, it is probably released from the nuclei of tumor cells during
apoptosis.
In various case-control and cohort studies, the sensitivity of BTA-TRAK ranges from 52% to 83%
[72,129,142-144]. However, in a recent study that
followed the recommendations of the European
Group on tumor markers, the sensitivity of the BTATRAK was 8% to 17% to detect both primary tumors
and recurrence [144]. As in the case of BTA-Stat, the
sensitivity of the BTA-TRAK is higher for detecting
high grade and high stage tumors [46,70-72]. Multicenter studies and cohort studies have shown that the
sensitivity of the BTA-TRAK test also varies
depending upon the cutoff limit used on the test [7072,144].
2. METHODOLOGY
The NMP-22 test, which is manufactured by
Matritech Inc. (Matritech, Newton, MA, USA), is a
quantitative microtiter sandwich ELISA that uses 2
antibodies, each of which recognizes a different epitope of the nuclear mitotic apparatus [6]. This assay
usually needs a laboratory with trained technicians
and is not a point-of-care test. Because the NMP-22
test is quantitative, it is important to note the cutoff
used in any particular study [6]. Although the manufacturer’s recommended cutoff value is 10
units/mL, variable cutoff limits ranging from 7 to 27
units/mL have been applied, depending on the opti-
Among patients with benign conditions, the specificity of the BTA-TRAK is low, about 50%. For
example, levels of bladder tumor antigen above 72
mU/mL are often obtained in patients with hematuria
[143]. The reason for this is that the BTA-TRAK test
also detects complement factor H, which is abun-
87
mum sensitivity and specificity of the receiver operating curve [141,149-151]. Recently, a point-of-care
NMP-22 assay has become available, which involves
addition of 4 drops of urine in a point-of-care device
and reading the results 30 to 50 minutes later [152].
nary WBC. They further recommended that the cutoff value for monitoring recurrence be set at 5.0
U/mL, which resulted in 48.8% sensitivity and
66.6% specificity. Sanchez-Carbayo et al. found
80.6% sensitivity and 92.6% specificity in 31 recurrent bladder cancer patients among 106 cases with a
previous bladder cancer history, and 65.0% sensitivity and 91.9% specificity in 24 recurrent bladder cancer patients among 126 cases under intravesical
adjuvant instillation therapy [162]. Although the
results were superior to voided cytology, Friedrich et
al. showed that 2 of 25 (8%) false positive patients
later suffered from tumor recurrence while 2 of 36
(5.6%) true negative patients had tumor recurrence,
indicating that an abnormal NMP-22 test is not predictive of future recurrence [163]. In summary, in
follow-up studies after endoscopic treatment, overall
sensitivity ranges from 45% to 81%, and specificity
ranges from 65% to 93% [153,130,135,162]. Lower
sensitivity in the follow-up setting than in freshly
diagnosed cases is presumably caused by a relatively higher percentage of low grade tumors with low
tumor volume among recurrent superficial tumors at
follow-up.
3. RESULTS
In most studies, the subjects were patients with
newly-diagnosed bladder cancer with no previous
history of urothelial cancers, and controls were
selected from patients with benign urologic conditions or those with hematuria with no evidence of
urothelial or other urologic cancers. The sensitivity
has ranged from 47% to 100%, most often falling
between 60% and 70% [69,125,131,153-160]. The
specificity is between 60% and 90%, depending on
the cutoff value used [69,125,131,149,153,154,156158]. The positive predictive value of this test has
been reported to be as low as 34% to as high as 76%,
while the negative predictive value varies from
77.9% to 98% [69,141,150,151,154]. It should be
noted that these studies mostly dealt with patients
without a history of bladder cancer treatment.
In general, the NMP-22 test has a higher sensitivity
than cytology, especially in the case of low grade and
stage tumors, because the test is less influenced by
tumor grade and stage. However, there is a slight
increase in sensitivity with increase in tumor grade.
For example, Del Nero found in grades 1, 2, and 3
urothelial cancer of the bladder, sensitivities of 69%,
86%, and 90%, respectively [158]. Others have
found similar results with the increasing T stage of
the tumor, with a sensitivity of 71% in stage Ta and
T1, increasing to 93% in stages T2 to T4 [161].
Analysis of all of the data clearly shows that the
NMP-22 test is superior to cytology for detection of
grade 1 and 2 bladder cancer in terms of sensitivity,
but that it offers lower specificity. To overcome this
low specificity, Sharma et al. evaluated the causes of
false positive tests in order to exclude patients with
these results from testing and, thus, improve the
specificity of the tests [157]. In 278 symptomatic
patients, including 34 (12%) confirmed bladder cancer cases, they showed an overall sensitivity and
specificity of 82.4% and 82.0%. They identified the
following 6 criteria for excluding patients: benign
inflammatory conditions (infections, etc.), renal or
bladder calculi, foreign bodies (stents or nephrostomy tubes), bowel interposition, other genitourinary
cancer, and instrumentation. When patients with
these problems were excluded, specificity increased
to 95.6%. With the same exclusion criteria, Ponsky
et al. also showed an increase in specificity to 99.2%,
whereas the overall sensitivity and specificity were
88.5% and 83.9% without the exclusions [69].
The usefulness of the NMP-22 test in monitoring
recurrences in treated bladder cancer patients was
assessed in several studies. Soloway et al. used
NMP-22 to predict tumor recurrence after
transurethral bladder tumor resection at subsequent
cystoscopy in 90 patients [153]. With the cutoff
value at 10 units/mL, they found 69.7% overall sensitivity and 78.5% specificity. In addition, the test
was 100% sensitive for detecting invasive tumors.
Boman et al. reported 45% sensitivity and 65%
specificity, and claimed that the low sensitivity and
specificity was due to the relatively small size of
recurrent tumors, indicating the usefulness of the
NMP-22 test for monitoring recurrence is questionable [135]. Miyanaga et al. reported 18.6% sensitivity and 85.1% specificity in 51 patients with recurrent tumors among 156 follow-up cases [130]. They
also concluded that the low sensitivity was due to the
small size of recurrent tumors and presence of uri-
At the present time, not many studies have been conducted on the point-of-care NMP-22 test. However,
recently in a large prospective multi-center study that
involved 1331 study individuals, the point-of-care
NMP-22 test had 55.7% sensitivity and 85.7% specificity to detect bladder cancer. As in the case of
NMP-22 ELISA, the sensitivity of the point-of-care
test also increased with tumor grade and stage [152].
88
Summary
between cancer and normal cells. The group has previously identified a series of these nuclear structural
alterations, characteristic of bladder cancer, which
are not found in individuals that do not have the disease [164]. One of these markers, BLCA-4 is found
throughout the bladder in people with bladder cancer, including both tumor as well as normal regions,
but is not found in the bladders of individuals without the disease. This marker, therefore, may reflect a
type of “field effect” that has been observed at the
genetic level by a number of investigators. Recent
studies by Dr. Getzenberg’s group have revealed that
this marker appears to be a transcriptional regulator,
which may play an active role in the regulation of
gene expression within bladder cancer [165].
The NMP-22 test may provide adjunctive information in monitoring bladder cancer recurrence.
Although sensitivity data appear promising, the
sensitivity is not high enough to eliminate current
cystoscopic evaluation in both fresh and followup patients. Because of the relatively low specificity, its routine use for the detection of bladder
cancer is not recommended. If use of this test is
limited according to certain exclusion criteria (see
above), the test may be valuable in the detection
of fresh bladder cancer or monitoring patients
with a previous history of bladder cancer.
d) BLCA-4 and BLCA-1
2. METHODOLOGY AND RESULTS
1. INTRODUCTION
Utilizing 2 different forms of ELISA, Konety et al.
has been successful in detecting BLCA-4 in the urine
of patients with bladder cancer. The first assay that
was developed was an indirect assay. Urine samples
from patients diagnosed with bladder cancer, along
with normal controls, were collected and tested with
the indirect ELISA that we developed. This assay
requires no stabilization. In the initial clinical trial of
106 individuals, using a prospectively-defined cutoff
based upon the first 3 tumor and normal samples, we
demonstrated a sensitivity of 96.4% and a specificity of 100% [164,166]. Furthermore, in this study the
authors demonstrated that this assay was able to
detect almost all of the individuals who were not
considered to be positive for bladder cancer by cytology. In order to examine the expression of this and
other markers in a high-risk population for the development of bladder cancer, the Getzenberg group has
been studying individuals with spinal cord injuries. It
is known that individuals with spinal cord injuries
have up to a 460-fold increased risk for developing
bladder cancer and as many as 1 in 10 individuals
with spinal cord injuries actually develop the disease
[167]. In addition, this population represents a difficult group in which to utilize bladder cancer markers
since the presence of cystitis and other types of
inflammation within the bladder is common.
One approach to identifying novel tumor markers
relies on trying to understand and utilize some of the
hallmarks of the bladder cancer cell, in order to
develop assays which detect protein components that
are specific for the disease. One of the fundamental
changes that occur in a cancer cell is alteration in cell
and nuclear shape. These alterations are utilized by
the pathologist to identify cancer cells on microscopic examination. All cancer cells undergo these characteristic changes, and they are considered to be
defining aspects of the tumorigenic process. Since
changes in nuclear shape are characteristic of the
cancer cell, Getzenberg et al. have focused on understanding nuclear structure as an underlying framework for the observed changes in nuclear shape. In
addition, it is known that a number of processes are
altered within the cancer cell that can be traced back
to changes within nuclear structure. In cancer cells, it
is common to find rearrangements, translocations,
and other chromosomal events, which are atypical
for normal cells. In addition, genetic instability, in
which genes that may be differentiation-related may
be turned off, whereas embryonic or other types of
genes may be turned on, is commonplace in the cancer cell. The hypothesis of the Getzenberg laboratory is that not only are changes in nuclear structure
reflective of the characteristic changes in nuclear
shape observed by the pathologist in a cancer cell but
that these changes in nuclear structure may also
result in some of the loss of fidelity of these nuclear
processes, which are known to rely upon nuclear
structure for organization and function. The group
has performed proteomic analysis of the nuclear
structural components, termed the nuclear matrix, in
order to determine differences in these components
While the indirect assay that was developed revealed
both high sensitivity and specificity, it was necessary
to develop a higher throughput test that did not
require urine precipitation and which used a sandwich assay taking advantage of monoclonal antibodies. This type of assay would provide for a higher
throughput clinical test. This assay neither requires
urine precipitation nor consideration of the amount
of protein that is found in the sample. Ideal charac-
89
Summary
teristics of a tumor marker include high sensitivity
and specificity for disease, accuracy, precision, rapid
turn-around time, and ease of measuring at a low
cost. In order to accomplish the rapid turn-around
time, it was necessary to develop the immunoassay
on straight voided urine samples rather than concentrating the proteins by ethanol precipitation. In tandem, a sandwich-based immunoassay was developed
by utilizing several antibodies (both monoclonal and
polyclonal) raised against BLCA-4. The advantage
of this assay is that any number of different sources
of antibodies can be added to the captured antigen,
provided that the species in which it was produced is
not the same as the capture antibody. More specifically, the enzyme conjugated anti-species antibody
should not react with the antibodies used to capture
the antigen.
BLCA-4 is a potentially useful marker for the
detection of bladder cancer, as it detects bladder
cancer with both high sensitivity and specificity.
BLCA-1 is another potentially useful marker for
bladder cancer that is currently under investigation. Large multi-center clinical trials will validate the efficacy of these potentially useful markers.
e) Survivin
1. INTRODUCTION
Survivin is an anti-apoptotic protein that is a member
of the inhibition of apoptosis protein (IAP) gene
family [170,171]. It is overexpressed in a wide range
of malignancies, including carcinoma of the bladder
urothelium, and it can be detected in the urine of
patients with bladder cancer. Various studies have
been performed on the relevance of survivin in the
diagnosis of bladder cancer. Ku et al. used immunohistochemistry to study the expression of survivin in
bladder cancer and found high expression of survivin
in 58% (51 of 88) of superficial bladder cancer cases
[172]. Lehner reported nuclear staining in 58% (26
of 45) of bladder cancer tissues and in 14.3% of CIS
tissues. No nuclear staining was observed in normal
bladder mucosa. Interestingly, patients with bladder
cancer and a nuclear pattern of survivin localization
had a greater period of disease-free survival (27.2
months) than was observed in patients with urothelial carcinoma that showed no nuclear staining for
survivin (9.9 months); however, the differences were
not statistically significant [173]. Gazzaniga et al.
used RT-PCR analysis and showed that the survivin
transcript is expressed in 30% of bladder tumor tissues [174]. Using similar analysis, Schultz et al.
found survivin mRNA expression in 100% of the
bladder tumor tissues examined [175].
In order to test the sandwich-based immunoassay on
populations of patients that would reflect specificity
and sensitivity issues for the detection of bladder
cancer, a large number of samples representing
unique patient groups were assayed [168]. This study
included patients with biopsy-confirmed bladder
cancer (Group A), individuals that had identified
benign urologic conditions (Groups B and C), individuals with the most prevalent urologic cancer,
prostate cancer (Group D), and normal individuals
(Group E). A training set was used to establish a cutoff that was then applied to the sample set being tested. The results from the trial, which examined 168
individuals, demonstrated a sensitivity of 89% and a
specificity of 100% in this complex mixture of samples [168]. A large national clinical trial is currently
underway to validate these studies and determine the
utility of this marker in diagnosing bladder cancer.
BLCA-4 is just 1 of the 6 nuclear structural proteins
that has been identified, which are expressed only in
bladder cancer. Many nuclear structural proteins
have now been sequenced. Meyers et al. have studied one such protein, BLCA-1, and found that it is a
potentially valuable marker for bladder cancer. The
expression of BLCA-1 is different from that of
BLCA-4 described above. BLCA-1 is expressed
only in the tumor areas of the bladder and is not
expressed in normal adjacent tissue or in normal
bladder tissue. An immunoassay which detects
BLCA-1 in straight urine samples from individuals
with bladder cancer with high sensitivity and specificity has been developed. The urine levels of this
marker also appear to be increased with higher tumor
stages, another distinction from BLCA-4 [169].
2. METHODOLOGY
The survivin urine test is a bio-dot test in which urine
samples are blotted as dots on nitrocellulose membranes, and survivin present in the samples is detected using a rabbit polyclonal anti-survivin antibody
and standard dot-blot detection reagents.
3. RESULTS
In initial studies with relatively small numbers of
patients with bladder cancer, the survivin dot-blot
assay had 100% sensitivity [176,177]. Its specificity
among normal individuals and patients with benign
genitourinary conditions is 100% and 87%, respec-
90
(both primary and recurrent) varies between 35%
and 79% [55,58,184-187]. In a retrospective casecontrol study, Boman et al. studied the effect of
tumor size, grade, and stage on the sensitivity of the
UBC-Rapid test [55]. The UBC-Rapid test had
slightly higher sensitivity (53%) to detect small new
tumors (≤ 10 mm) than to detect small recurrent
tumors. The difference between the detection of new
versus recurrent tumors was most striking in TaG1
and TaG2 tumors. Consistent with these observations, several studies have also reported lower sensitivity of UBC to detect low grade and low stage
tumors. The sensitivity of UBC to detect G1, G2, and
G3 bladder tumors is 13% to 60%, 42% to 79%, and
35% to 75%, respectively [55, 57, 58, 182-184]. In
retrospective cohort studies, Mungan et al. and
Schroeder et al. reported 21% to 25% sensitivity of
UBC-Rapid to detect stage Ta tumors and CIS.
Mungan et al. concluded that the UBC has insufficient diagnostic value for detecting superficial bladder cancer [57]. In studies that compared different
bladder tumor markers, UBC tests had lower sensitivity than other markers, including cytology [55, 57,
58, 182, 183, 185, 187,188].
tively [7,8]. Recently, Shariat et al. showed that
higher urinary survivin levels are associated with
increased risk of bladder cancer and higher grade
tumors [178]. In that study, which involved 117 bladder cancer patients and 97 controls, the survivin-dotblot assay had 64% sensitivity and 93% specificity.
In a study of 25 patients, Hausladen reported that
urinary survivin levels were higher in patients in
whom urothelial carcinoma recurred compared with
those who achieved remission after treatment with
BCG or mitomycin C [179]. In this study, survivin
had 100% sensitivity and 78% specificity. In addition to the survivin dot blot assay, Schultz et al. have
used RT-PCR on exfoliated cells to detect survivin
mRNA expression in bladder washing specimens.
Their results show that survivin mRNA copy number
is a predictor of bladder tumor recurrence [180].
Summary
A limited number of studies show that survivin
may be a potentially useful marker in the detection of bladder cancer. However, more cohort studies are needed to evaluate this marker.
In addition to the UBC tests, a combined use of DNA
and cytokeratin 8 and 18 flow-cytometry on exfoliated cells, together with the measurement of cytokeratin 8 and 18 levels by UBC for detecting recurrent
bladder cancer has been suggested [187]. This technique increased the sensitivity of UBC from 77%
when used alone, to 89% when used in combination
with DNA analysis. However, the combination had a
higher false positive rate among individuals with
benign urological diseases and patients undergoing
intravesical therapy [187]. In most studies, the specificity of UBC test varies between 65% and 75%
f) Cytokeratins
Cytokeratins are intermediate filament type
cytoskeletal proteins that have been tested as bladder
tumor markers in many studies. In human cells, a
total of 20 cytokeratins have been identified and their
expression reflects the type and differentiation state
of the epithelial cells [181]. The expression of cytokeratins 8, 18, 19, and 20 at the protein or mRNA level
has been evaluated as a bladder cancer marker. Since
cytokeratins are intracellular proteins, the detection
of these proteins in urine is possible only when they
are released in urine following cell death. UBC tests
and CYFRA 21-1 are urine tests that detect cytokeratin 8 and 18 and a cytokeratin 19 fragment, respectively. There is no test that detects soluble cytokeratin 20 protein in urine. Cytokeratin 20 mRNA
expression is detected by RT-PCR in exfoliated cells
in urine or in bladder wash specimens.
2. CYTOKERATIN 20
The expression of cytokeratin 20 is restricted to
superficial and, occasionally, intermediate cells of
the normal urothelium [1]. Aberrant cytokeratin 20
expression is present in bladder cells and in other
urothelial cancer cells [181]. Immunohistochemistry
and RT-PCR techniques have been used to evaluate
the expression of cytokeratin 20 at the protein and
mRNA level in bladder tissues and exfoliated cells.
In a prospective cohort study involving only bladder
cancer patients, Harnden et al. observed that cytokeratin 20 expression examined by immunohistochemistry could be used to distinguish between noninvasive papillary urothelial tumors that recur and
those that do not [189]. In this study, the only factor
that had a significant effect on the outcome of
patients in terms of recurrence was cytokeratin 20
1. UBC TESTS
UBC-Rapid and UBC-ELISA tests manufactured by
IDL Biotech, Borläbger, Sweden, detect the presence
of cytokeratin 8 and 18 in the urine of bladder cancer
patients [182,183]. UBC-Rapid is a point-of-care
test, whereas UBC-ELISA (i.e., UBC-IRMA) is a 2hour sandwich ELISA test. The manufacturer suggested cutoff limit for UBC-IRMA is 12 ng/mL. In
several retrospective cohort and case-control studies,
the sensitivity of UBC tests to detect bladder cancer
91
[100]. Thus, although cytokeratin 20 immunocytology improves the overall sensitivity of cytology, this
technique still misses 43% of low grade bladder
tumors. Since the sensitivity of cytology to detect
high grade tumors is high, an added value of cytokeratin 20 immunocytology may be justified only if it
can improve the sensitivity of cytology for detecting
low grade bladder tumors.
expression [189]. McKenney et al. have suggested
the use of cytokeratin 20 along with p53 as immunohistochemical markers for distinguishing CIS from
reactive atypia [190].
In mostly case-control retrospective studies, cytokeratin 20 expression in bladder cancer patients has
been studied using an RT-PCR assay [191-196]. In
these studies, cytokeratin 20 RT-PCR has 78% to
87% sensitivity to detect bladder cancer with a
strong correlation between tumor keratin and cytokeratin-positive tumor cells in urine [191-195]. In
addition, Rotem et al., in a case-control retrospective
study, reported that 44% of the false positive cases
detected by the cytokeratin 20 RT-PCR assay
recurred within 6 months [192]. The specificity of
cytokeratin 20 RT-PCR among healthy individuals
and patients with clinical conditions other than bladder cancer varies between 55.7% and 80% [191195]. Finding that cytokeratin 20 can a have false
positive rate of 44.3%, Cassel et al. concluded that
cytokeratin 20 expression is not specific for malignancy, and, therefore, its use as a potential marker for
bladder cancer should be carefully evaluated [193].
3. CYFRA 21-1
Cytokeratin 19 is expressed in normal urothelium.
Since urothelial cells exfoliate, lysed cells release
cytokeratin 19 in urine [1]. CYFRA 21-1 is a soluble
fragment of cytokeratin 19 that is measured either by
a solid phase sandwich immunoradiometric assay
(Cis Bio international, Gif-sur-Yvette, France) or an
electrochemiluminescent immunoassay with the
Elec sys 2010 system (Roche Diagnostics), and the
levels of cytokeratin 19 are normalized to urinary
creatinine [104]. Pariente et al., in a retrospective
cohort study, found that CYFRA 21-1 levels in bladder cancer patients, patients with other urologic conditions, and normal controls are 154.4 ng/mL, 22.3
ng/mL, and 2.4 ng/mL, respectively [197]. Using a
cutoff value of 4 ng/mL, the sensitivity and specificity of CYFRA 21-1 assay to detect bladder cancer
were 96.9% and 67.2%, respectively. In this study,
patients with urolithiaisis and urinary tract infection
had high urinary levels of cytokeratin 19. In another
study, Sanchez-Carbayo et al. reported 75.5% sensitivity and 71% specificity for detecting bladder cancer; using the electrochemiluminescent assay for
measuring CYFRA 21-1 levels [197]. In this study,
the sensitivity of the CYFRA 21-1 test to detect G1,
G2, and G3 tumors was 54.5%, 66.7%, and 88.2%,
respectively. However, in various urologic conditions such as urolithiasis, stenosis, benign prostate
hyperplasia, and urinary tract infections, the false
positive rate is around 33%.
The cytokeratin 20 RT-PCR assay is found to detect
as few as 2 bladder cells per milliliter of blood and
has been suggested as a promising approach for the
early detection of systemic progression of bladder
cancer [191]. However, Gazzaniga et al. found that
blood samples from only 17% of bladder cancer
patients were positive for cytokeratin 20 on RT-PCR
[195]. In addition, the high sensitivity of any RTPCR assay using peripheral blood may also be associated with low specificity [193].
Cytokeratin 20 immunocytochemistry has been evaluated as an adjunct marker for atypical cytology. For
example, in a retrospective cohort study, Lin et al.
reported that cytokeratin 20 immunocytochemistry
detected bladder cancer in atypical cytology cases
with biopsy proven bladder cancer with 94.4% sensitivity. The false positive rate of this staining was
37.8% [196]. Golijanin et al., in a cohort of new
patients presenting with microhematuria and patients
with a history of bladder cancer, also reported a high
sensitivity (82%) and specificity (76%) for detecting
bladder cancer using 5% cytokeratin 20 positive cells
as the cutoff limit to detect bladder cancer [100].
The sensitivity of cytokeratin 20 was very similar in
detecting primary and recurrent tumors. However, in
this study the sensitivity to detect bladder cancer
according to tumor grade was 56.5%, 93%, and 92%
for G1, G2, and G3 bladder tumors, respectively
Summary
Based on several cohort and case-control studies,
UBC tests appear to have low sensitivity to detect
both low grade and low stage tumors. The overall
sensitivity of these tests is also lower than several
other bladder tumor markers. In addition, cytokeratin markers show high false positive rate among
individuals with a wide range of clinical disorders.
Based on the conclusions of case-control studies,
detection of cytokeratin 20 by RT-PCR
assay, immunocytology, or immunohistochemistry
92
ng HA/mg protein. For the HA test, urinary HA levels ≥ 500 ng/mg (cutoff limit) constitute a positive
test [198,204].
appears to be a useful marker to detect bladder cancer. However, lower specificity of cytokeratin 20
markers reported in some studies indicate that the
identification of benign conditions that cause aberrant expression of cytokeratin 20 may help to
improve the clinical applicability of this marker. In
addition, cytokeratin 20 immunocytochemistry
may not improve the sensitivity of cytology in
detecting low grade tumors.
The HAase test measures HAase activity in urine.
HAase present in urine degrades HA that is coated on
microtiter well plates. Following incubation, the
degraded HA is washed off and the HA remaining on
the microtiter well plates is measured using the same
biotinylated HA binding protein and the avidinbiotin detection system as the HA test. Urinary
HAase levels (mU/mL) are determined from a standard graph and normalized to total urinary protein
(mg/mL). For the HAase test, urinary HAase levels
at or above 10 mU/mL constitute a positive test
[198,199,207].
At the present time, there is limited data available
on CYFRA 21-1 and thus recommendations cannot
be made on this marker. In addition, this marker
may have high false positive rate in various benign
urologic conditions.
In general, the utility of cytokeratin markers for
detecting bladder cancer will depend upon improving the sensitivity of these markers to detect low
grade tumors and reducing the high false positive
rate seen in several urologic conditions other than
bladder cancer.
3. RESULTS
In an initial case-control study, urinary HA, measured using the HA test, was found to be elevated
2.5- to 6.5-fold in patients with bladder cancer,
regardless of tumor grade [8]. HAase levels measured using the HAase test were preferentially elevated (three- to sixfold) in the urine of patients with
G2 and G3 bladder cancer [207]. In a case-control
study involving 504 individuals (261 bladder cancer
patients and 243 control individuals), the HA test had
83.1% sensitivity and 90.1% specificity to detect
bladder cancer, regardless of the tumor grade [199].
In the same study, the HAase test had 81.5% sensitivity and 83.8% specificity for detecting G2 and G3
bladder cancer. Combining these 2 tests into the HAHAase test resulted in bladder cancer detection with
higher overall sensitivity (91.9%), with 86.4%,
95.7%, and 93.3% sensitivity to detect G1, G2, and
G3 bladder tumors, respectively (Level 3, [199]).
The HA-HAase test also detected both superficial
(stages Ta, T1, and CIS) and invasive (stages ≥ T2)
tumors with 87% to 100% sensitivity, respectively.
The overall specificity of the HA-HAase test in this
study was 84% [199]. The control population included normal healthy individuals; patients with genitourinary conditions such as stone disease, BPH,
microhematuria, urinary tract infection, and cystitis;
and patients with a history of bladder cancer but no
evidence of disease at the time of testing. In a retrospective cohort study involving 83 bladder tissues
and 34 urine specimens, Hautmann et al. demonstrated a close correlation between elevated HA and
HYAL1 levels in bladder tumor tissues and a positive
HA-HAase urine test. The authors concluded that in
patients with bladder cancer tumor-associated HA
and HYAL1 are secreted in urine, which results in a
positive HA-HAase test [208].
g) HA-HAase Test
1. INTRODUCTION
This test measures urinary levels of hyaluronic acid
(HA) and hyaluronidase (HAase) using 2 very similar ELISA-like assays [38,198,199]. HA is a glycosaminoglycan that regulates cell adhesion, migration, and proliferation [200,201]. HA is known to
promote tumor metastasis, and its concentration is
elevated in several tumors including colon, esophagus, breast, prostate, and bladder [198,201,202].
Small fragments of HA are angiogenic and are generated when HAase degrades HA [203]. HA fragments are detected in the urine and tumor tissues of
patients with high grade bladder cancer [202,204,
205]. HYAL1-type HAase has been shown to be the
major tumor-derived HAase secreted by tumor cells
[202,204,206].
2. METHODOLOGY
The HA test is based on the competition binding
principle, in which HA present in urine competes
with HA-coated microtiter wells to bind to a biotinylated bovine nasal cartilage HA-binding protein. Following incubation, the unbound HA-binding protein
is washed off, and the HA-binding protein bound to
microtiter wells is measured using an avidin-biotin
detection system [199]. The HA present in each urine
sample (ng/mL) is determined from a standard
graph. To account for differences due to the hydration status of individuals, urinary HA levels are normalized to total urinary protein and are expressed as
93
The ability of the HA-HAase test to monitor bladder
cancer recurrence was compared with that of BTAStat in a prospective cohort study of patients with
recurrent bladder cancer [38]. In this study, the HAHAase and BTA-Stat tests had 94% and 61% sensitivity, 63% and 74% specificity, and 87% and 64%
accuracy, respectively. More interestingly, a false
positive HA-HAase test carried a tenfold increased
risk (risk ratio = 10.2) for tumor recurrence within 5
months, whereas a false positive BTA-Stat test did
not carry any statistically significant risk for tumor
recurrence within the same time frame (risk ratio =
1.4) [38].
Summary
Recently, 2 retrospective cohort studies compared
the accuracy of the HA-HAase test with cytology
and biomarkers such as BTA-Stat, hematuria detection, UBC-Rapid, and Immunocyt [58,64]. In the
study by Schroeder et al., involving 138 urine specimens, HA-HAase test, cytology, BTA-Stat,
hemoglobin dipstick, and UBC-Rapid had 88.1%,
70.6%, 52.5%, 50.8%, and 35.6% sensitivities,
respectively (Level 2, [58]). The tests had 81% (HAHAase), 81% (cytology), 76.7% (BTA-Stat), 78.2%
(hemoglobin dipstick), and 75% (UBC-Rapid) specificities [13]. Among various tests and cytology, the
HA-HAase test had the highest sensitivity in detecting both low grade, low stage and high grade, high
stage tumors. Hautmann et al., in a study of 94 consecutive patients, found that the sensitivity of the
HA-HAase urine test (83.3%) was significantly
higher than the Immunocyt (63%) [64]. In that study,
both tests had comparable specificity (HA-HAase
78.1%; Immunocyt 75%). The combination of both
the HA-HAase and Immunocyt tests had 93.3% sensitivity without a significant decrease in specificity
[64].
a) Microsatellite Analysis
Case-control and cohort studies show that the
HA-HAase test is a promising method for detecting new onset and recurrent bladder tumors. The
test has high sensitivity to detect low grade, low
stage and high grade, high stage tumors. This test
may also be useful in screening a high-risk population for bladder cancer. The accuracy of this test
needs to be evaluated in larger multicenter trials.
2. CELL-BASED MARKERS
1. INTRODUCTION
Microsatellites are highly polymorphic short tandem
DNA repeats (mostly 2 to 4 base pairs each) found
throughout the human genome [210]. Two types of
“microsatellite alteration” can be found in many cancers. One is the loss of heterozygosity (LOH=allelic
deletion), which is a hallmark of inactivation of
tumor suppressor genes and can be detected in exfoliated cancer cells in urine, as well as in bladder
tumor tissues [211-213]. The other is a somatic alteration of microsatellite repeat length in cancer cells,
which can be detected as “microsatellite instability”
or “a new allele” [211-213]. “LOH” and “microsatellite instability” can be used as markers of neoplasia
and are known as “microsatellite alteration.”
One of the most common genetic changes in bladder
cancer is LOH on chromosome 9 [214]. Chromosomes 4p, 8p, 9p, 11p, and 17p also often display
LOH in bladder cancer [214-217]. While LOH on
chromosome 9p and 9q is found regardless of tumor
grade and stage, LOH on other chromosomes is generally detected more frequently in tumors with higher grade or stage. Microsatellite instability can be
detected as a result of genomic instability in cancer
cells. Although microsatellite instability tends to be
found more frequently in advanced bladder cancers,
it was found frequently in low grade, low stage
tumors when more microsatellite markers were used.
Srougi et al. compared accuracy of the HA test
(hyaluronic acid detection test part of the HA-HAase
test), UroVysion, BTA-Stat, and cytology in a
prospective study involving bladder cancer patients
with either primary or recurrent tumors [209]. The
specificity of these tests was determined in patients
with a history of bladder cancer but no evidence at
the time of testing and in patients with benign
prostate hyperplasia. The sensitivity of the HA test
was the highest (83%) followed by BTA-Stat (75%),
UroVysion (73%), and cytology (67%). The combination of HA test with UroVysion had 95% sensitivity to detect bladder cancer. The specificity of all of
the tests were comparable to each other, although the
HA test had slightly higher specificity than all of the
tests.
2. METHODOLOGY
To detect microsatellite alterations in the urine of
patients with bladder cancer, DNA is extracted from
cells in urine sediment, and then the samples are analyzed with PCR using DNA primers for a panel of
known microsatellite markers. It has been reported
that detection of microsatellite instability requires a
ratio of tumor DNA to contaminating normal DNA
94
of more than 0.5% [217], whereas the detection of
LOH requires at least 20% tumor DNA [218]. Generally, the more microsatellite markers used, the
higher the sensitivity achieved. In addition, the number of loci at which LOH is found in bladder cancer
increases as tumor grade or stage increases [214216]. As for microsatellite instability, it also tends to
be found more frequently in advanced cancer [219222]. It is important to use a substantial number of
microsatellite markers (15 to 20) at different loci to
achieve high sensitivity.
Using a DNA chip (HuSNP chip) that can discriminate different alleles by single nucleotide polymorphisms, the presence of LOH at nearly 1500 loci can
be examined at once. Although experimental at present, Hoque et al. demonstrated that LOH at 24 or
more loci could be detected with 100% sensitivity in
31 patients, while the alterations were not found in 9
control subjects and 4 of 5 patients with hematuria.
[235]. Using a DNA chip assay is a promising
method for detection of genomic alterations from
urine specimens.
3. RESULTS
While the mutation of known oncogenes and tumor
suppressor genes could be detected from urine specimens [236,237], the complicated methodology hampers its routine clinical application. Nonetheless, it
has been demonstrated that tumor-specific hypermethylation at CpG sites can be detected by methylation-specific PCR, which may be able to detect only
0.1% to 0.001% of tumor cells among normal cells
[238]. However, the methodology is still time-consuming and requires expensive equipment and
trained personnel at present.
Several case-control studies, which analyzed voided
urine specimens using 13 to 60 microsatellite markers, have been conducted. However, in most of these
studies 15 to 20 microsatellite markers were used
[56,213,222-234]. The overall sensitivity from these
studies was 72% to 97% and overall specificity was
80% to 100%. One study indicated that the presence
of cystitis or BPH may cause false positive results
[221]. Although these studies demonstrated high sensitivity and specificity, all involved small numbers of
patients, particularly in the control groups. Therefore, it remains to be clarified whether high specificity is maintained even in patients with benign
inflammatory or neoplastic diseases.
Summary
Microsatellite analysis demonstrates excellent
sensitivity and specificity, independent of tumor
grade and stage, tumor multiplicity, or previous
history of bladder cancer. In spite of the superiority of this analysis, a need for expensive equipment
and trained personnel with up-to-date techniques
and protocols hampers the routine use of this analysis in clinical settings. To date, no results from a
large-scale prospective study have been published.
If the analysis can be automated and replicated by
others, it might have a significant role in urinebased bladder cancer screening or follow-up. A
large-scale prospective study employing automated analysis of a panel of microsatellite markers
has recently been initiated through the NCI Early
Detection Research Network in the USA. At present, microsatellite analysis of urine is experimental and not recommended for either detection or
follow-up in routine clinical settings.
As for tumor grade and stage, one study indicated
that sensitivity increased somewhat as grade and
stage became higher [226]. In addition, van Rhijn
found that microsatellite markers missed all of the 11
Ta tumors that were included in the study [56]. However, in most studies an association between the sensitivity, tumor grade, and stage was not observed.
Since the number of loci with microsatellite alterations found in each case increases in higher grade or
stage tumors, it is, again, important to use an appropriate number (15 to 20) of microsatellite markers.
As for the follow-up settings, high sensitivity was
observed consistently in both primary and recurrent
tumors [56, 222, 226].
4. NOVEL METHODOLOGY
More recently, activating FGFR3 mutations have
been shown to be detected frequently in low grade
superficial bladder caners [220]. Van Rhijn et al.
showed that the combination of microsatellite analysis and the FGFR3 mutation analysis enhanced the
sensitivity of the urine detection system and the sensitivity was 89%, compared with 71% for negative
FGFR3 mutations [220]. The study also demonstrated no relationship between the test positivity and
tumor grade and stage and multiplicity [220].
b) Telomerase
1. INTRODUCTION
Telomeres are nucleotide sequences at the 3’ end of
the lagging (5’ to 3’) strand of DNA that remain
uncopied after each cycle of DNA replication [239].
In mammals, an array of tandem repeats of the
95
negative, several variations to this protocol have
been proposed to improve the sensitivity of the assay
and transform this qualitative method into a procedure for obtaining quantitative information on telomerase activity [245,246].
sequence TTAGGG forms telomeres, which are specialized heterochromatin structures that act as protective caps at the end of chromosomes [240]. The
function of telomeric sequences is believed to be
protection of chromosomal ends and maintenance of
genomic stability.
Besides the TRAP assay, 3 major components of
human telomerase - human telomerase RNA
(hTERC), telomerase-associated protein (TEP1), and
a catalytic subunit of telomerase (hTERT) - have
been identified [247]. The gene cloning of these
components enabled a different approach to the
detection of telomerase activity based on the measurement of specific mRNA by an RT-PCR technique. Although the relationship between the expression of this mRNA and enzyme activity has not been
completely elucidated [248], hTERT mRNA expression is closely associated with telomerase activity
and is a rate-limiting determinant of telomerase
[247-250].
Telomerase is a ribonucleoprotein that catalyzes the
addition of telomeric repeats to the 3’ end of chromosome DNA [241], thereby preventing the loss of
telomeric sequences, reconstituting the ends of chromosomes after cell division and circumventing the
damage that occurs in normal adult somatic cells
during successive mitosis. This enzyme is a complex
containing a protein subunit and an RNA component.
The RNA subunit of human telomerase, called hTER
or hTR, provides the template for telomeric repeat
synthesis. The active site of the protein subunit contains the catalytic activity of the enzyme called
hTERT in humans, and is functionally homologous
to the reverse transcriptase (RT) of retroviruses
[241].
3. RESULTS
• Application in Urothelial Cancer
Telomerase is active during human embryogenesis,
but downregulated at tissue differentiation [242]. In
normal tissues, low levels of telomerase activity
have been found in proliferating cells [4]. More than
90% of human cancer is telomerase-positive, whereas most normal tissues or benign tumors contain low
or undetectable telomerase activity [243]. From
these results, many investigators have tried to use the
presence of telomerase activity as a novel and useful
tumor marker with a relevant diagnostic capability.
• General Description
Studies have demonstrated that telomerase may be
detected in bladder cancer tissue and in the urine of
patients with bladder cancer. Telomerase activity has
been shown to be present in more than 85% (mostly
over 90%) of bladder cancer tissues, regardless of
tumor grade and stage [251-255].
Telomerase activity in exfoliated cells collected in
normally voided urine or in bladder washings can be
detected using this highly sensitive TRAP assay. The
overall sensitivity of urine-based TRAP assays for
detection of bladder cancer is mostly between 70%
and 90% [125,149,252,256-258], although much
lower sensitivity was reported in some studies [255,
259,260].
2. METHODOLOGY
An important improvement in telomerase detection
was the development of the telomeric repeat amplification protocol assay (TRAP assay) [244]. This highly sensitive assay is based on polymerase chain reaction (PCR) amplification of in vitro telomerase reaction products. First, TTAGGG repeats are synthesized and amplified by PCR utilizing the telomerase
in target tissues or specimens [244]. The PCR products are then analyzed on gels. Commercially available kits (the TRAPeze by Appligene® Oncor and a
kit by Boehringer Mannheim) provide optimized sets
of primers and reagents for telomerase detection.
The test must be done in a reference laboratory with
specialized equipment and trained personnel.
Because the TRAP assay is a complex procedure
with a PCR amplification step, it is particularly sensitive to potential inhibitors of PCR reaction, therefore causing false negative results.
Generally, the TRAP assay has shown better sensitivity than cytology, with slightly lower specificity
[150, 255]. When patients with inflammatory conditions or benign urologic disease are included as normal controls, specificity may be lower because of the
contaminating benign cells with telomerase activity
(for example, lymphocytes). It should be noted that
most of the above studies were performed on patients
with documented bladder cancer (mostly fresh cases)
as positive controls.
• Detection of Recurrent Bladder Cancers
Only a few studies have focused on telomerase
detection in the follow-up setting after endoscopic
treatment. In 42 patients with a previous history of
Because the conventional TRAP assay provides
qualitative information only, that is, positive versus
96
bladder cancer, a low sensitivity of 29% (10 of 35)
was found by the TRAP assay using voided urine
[261]. Low sensitivity (35%) in follow-up settings
was also reported by Dalbagni et al. [259]. Although
Wu et al. suggested that the recurrence rate for
patients with a positive TRAP assay using urine after
transurethral resection (TUR) was higher than that of
those with negative activity (50% vs. 17.7%), they
later reported that the positive telomerase activity
after TUR was not associated with recurrence [260,
262]. Although the telomerase assay demonstrated
high sensitivity in a cohort of documented fresh
bladder cancer patients, it is not known whether this
high sensitivity is achieved in follow-up settings, in
which most of the recurrent tumors are small and of
low grade.
sourgos et al. [267]. Although the sensitivity of the
hTERT mRNA detection by RT-PCR seems to be
higher, it should be noted that substantial variation in
the sensitivity and specificity still occurs according
to the sample collection and processing procedures,
RT-PCR conditions, and the presence of RT-PCR
inhibitors or non-malignant cells in urine samples.
Summary
Despite the excellent results of telomerase detection using the TRAP assay, some problems have
hampered its widespread use in clinical settings.
Telomerase was not grade sensitive, but false
positive results were obtained in cases of chronic
or severe bladder inflammation due to the presence of lymphocytes. False negative results may be
obtained depending on the sample collection and
processing procedures, and the presence of PCR
inhibitors or ribonuclease [268]. Basically, telomerase detection requires immediate urine processing within 24 hours. Since at least 50 cells
expressing telomerase are required to ensure
reliable detection of telomerase by the TRAP
assay [252], tumor volume may be one of the
significant determinants of sensitivity, and there
will be a higher rate of false negative results
when detecting small tumors, especially in follow-up settings after endoscopic treatment.
Improvements in the assay technique (for
example, hTERT mRNA detection by a real timequantitative RT- PCR assay) and adherence to
more stringent conditions should address these
problems in the future.
• Voided Urine or Bladder Washings?
In a few studies, the sensitivity of the TRAP assay
was compared between voided urine and bladder
washing fluid. While Kinoshita et al. showed a significantly higher sensitivity using bladder washings
than voided urine (55% vs. 84%) with no difference
in specificity [255], Gelmini et al. showed no difference between the 2 groups (82% in both) [15]. Higher sensitivity using bladder washings was also
observed in another study [263].
• Alternative Methods to the TRAP Assay
As described before, recent molecular cloning of the
telomerase components enabled a different approach
to the detection of telomerase activity, that is, the
measurement of specific mRNA by an RT-PCR technique. Although the relationship between the expression of each mRNA and enzyme activity has not
been completely elucidated [248], the hTERT
mRNA expression is well associated with telomerase
activity and is a rate-limiting determinant of telomerase [247,249,250]. Bialkowska-Hobrzanska et al.
showed that hTERT mRNA detection in urine specimens had a higher sensitivity than the conventional
TRAP (94.3% vs. 48.6%), with a slightly lower
specificity (92% vs. 100%) [264]. Using washing
fluid specimens, Isurugi et al. showed that overall
sensitivity for hTERT detection by RT-PCR was
75.6%, varying from 52%, 80%, and 94% for grade
1, 2, and 3 tumors, respectively [265]. Using a real
time-quantitative RT-PCR assay for hTERT mRNA,
de Kok et al. reported that both 100% sensitivity and
specificity were achieved, and a higher hTERT
mRNA level was found in tumors with higher grade
and stage [266]. High sensitivity (92%) and specificity (94%) with hTERT mRNA detection from
voided urine samples were further reported by Melis-
c) uCyt™
1. INTRODUCTION
Immunocytology is based upon the visualization of
tumor-associated antigens in urothelial carcinoma
cells using monoclonal antibodies. Over the last 2
decades, a variety of monoclonal antibodies have
been evaluated for their potential in the diagnosis of
bladder cancer. Today, the uCyt™ assay is the most
frequently used immunocytological test.
2. METHODOLOGY
uCyt™ is a commercially available immunocytological assay based upon microscopic detection of
tumor-associated cellular antigens in urothelial cells
by immunocytochemistry (Diagnocure Inc., Quebec,
Canada). Triple antibody labeling is performed using
fluorescein-labeled monoclonal antibodies M344
and LDQ10 directed against sulfated mucinglyco-
97
proteins and a Texas-red linked monoclonal antibody
19A211 against glycosylated forms of high molecular carcinoembryonic antigens (hmCEA). Specific
technical requirements for this assay are a high quality fluorescence microscope and a cytocentrifuge.
Apart from this, the assay can easily be performed
even in smaller peripheral laboratories. On-site training, significant experience, and regular quality control are mandatory. The time-consuming microscopic examination of the slides remains a disadvantage.
Despite the observer-dependence, reproducibility is
good.
sons for these differences may be manifold and
largely due to patient selection. However, it should
be noted that immunocytology is an observer-dependent technique requiring a broad personal experience
and constant quality control [269]. This may be one
explanation for the observation that those groups
performing this test on a routine basis tend to have
results superior to those with a limited experience.
Summary
With an average sensitivity and specificity of
approximately 80%, the uCyt assay is superior
to conventional urine cytology and clearly
belongs in the group of the most promising diagnostic markers for bladder cancer. A prospective
evaluation to further assess the role of this test in
the management of bladder cancer appears worthwhile.
3. RESULTS
Several reports addressing the test performance have
been published (Tables 2 and 3). Analyzing the
results reported for immunocytology, the broad variation specifically concerning test sensitivity ranging
between 38% and 100% is remarkable (Table 3).
Specificity ranges between 75% and 90%. The rea-
Table 2. Sensitivity and Specificity of Immunocytology (uCyt™) and Cytology in the Diagnosis of Bladder Cancer: Summary
of Literature
Sensitivity/Specificity (%)
n
uCyt™
Author (year)
Stage/grade
Mian et al. (1999) [270]
G1
G2
G3
Controls
25
25
29
135/167
84
88
97
79
Olsson and Zackrisson (2001) [271]
G1
G2
G3
Negative
8
14
8
83
100
100
100
69
NR
Lodde et al. (2003) [272]
G1
G2
G3
Controls
20
18
13
40
85
100
92
80
5
55
85
96
Feil et al. (2003) [273]
Ta low grade
T1 high grade
T2 high grade
Controls
11
8
7
87
18
38
71
84
27
38
43
92
Pfister et al. (2003) [109]
G1
G2
G3
Controls
31
40
68
162/170
61
76
77
84.7
18
46
64
93.2
Hautmann et al. (2004) [64]
G1
G2
G3
Controls
4
15
11
64
75
47
82
75
50
53
82
80
Schmitz-Dräger et al. (2004)*
G1/2 (LMP)
G3
Controls
7
9
144
71
89
90
NR
NR
NR
* - personal communication, NR – not reported
98
Cytology
4
52
79
98
55
Table 3. Overall Sensitivity and Specificity of Immunocytology (uCyt™) and Cytology in the Diagnosis of Bladder Cancer:
Summary of Literature
Author (year)
Sensitivity (%)
Specificity (%)
uCyt™
Cytology
uCyt™
Cytology
Mian et al. (1999) [270]
68/79 (86)
37/79 (47)
107/135 (79)
164/167 (98)
Olsson and Zackrisson (2001) [271]
30/30 (100)
16/30 (55)
57/83 (69)
NR
Lodde et al. (2003) [272]
47/51 (92)
22/51 (43)
32/40 (80)
38/40 (96)
Pfister et al. (2003) [109]
101/139 (73)
67/139 (48)
137/162 (85)
158/170 (93)
Feil et al. (2003) [273]
10/26 (38)
9/26 (35)
73/87 (84)
80/87 (92)
Hautmann et al. (2004) [64]
19/30 (63)
22/30 (73) 4
3/64 (75)
51/64 (80)
Present series (2004)
13/16 (81)
NR
129/144 (90)
NR
Overall
288/371 (78)
173/355 (49)
578/715 (81)
491/528 (93)
Fradet et al. (2002) [274]*
394/438 (90)
235/438 (54)
760/1055 (72)
NR
NR – not reported, * - Combined analysis of 5 trials
ogy were assessed in routine alcohol-fixed specimens. The overall sensitivity for cytology and DD23
was 66% and 81%, respectively. The specificity of
cytology and DD23 was 85% and 60%, respectively.
The combination of cytology and DD23 had a sensitivity of 85%, specificity of 55%, positive predictive
value of 43%, and negative predictive value of 90%.
Combining DD23 with cytology increased the sensitivity for both low grade and high grade bladder cancers. For low grade cancers, the sensitivities of cytology, DD23, and the combination were 32%, 72%,
and 76%, respectively. For high grade cancers, the
sensitivities of cytology, DD23, and the combination
were 85%, 87%, and 95%.
d) DD23
1. INTRODUCTION
A monoclonal antibody called DD23 was first reported in 1992 [275]. This IgG1 murine monoclonal antibody resulted from the immunization of a BALB/c
mouse with a fresh human bladder cancer. Initial
results demonstrated binding to 32 of 40 bladder cancers and 9 of 16 breast cancers. It did not bind to normal ureter or bladder.
2. METHODOLOGY AND RESULTS
Initial clinical evaluation utilized quantitative fluorescence image analysis (QFIA). In a case-control
study, DD23 testing by QFIA was evaluated on voided urine from 41 asymptomatic controls, 34 symptomatic controls, and 41 patients with bladder cancer
[276]. The sensitivity for bladder cancer was 85%
with a specificity of 95%. No significant difference
was seen between symptomatic and asymptomatic
control populations, including patients with a history
of bladder cancer who were free of disease.
A single institution cohort study evaluated DD23 and
cytology in 151 specimens from 81 patients with a
history of urothelial carcinoma of the bladder [277].
A positive DD23 assay was defined as the presence
of 3+ chromogenic cytoplasmic staining in at least
one urothelial cell. The overall sensitivity of cytology, DD23, and the combination was 44%, 70%, and
78%, respectively. The overall specificity of cytology, DD23, and the combination was 92%, 60%, and
59%, respectively. Cytology, DD23, and the combination exhibited higher sensitivity but lower specificity in bladder barbotage specimens compared with
voided urine specimens. DD23 exhibited a sensitivity of 95% and a specificity of 33% in patients with a
history of intravesical therapy.
UroCor, Inc. licensed the DD23 monoclonal antibody, and the analytic method was converted to an
alkaline phosphatase immunohistochemical assay. In
2002, a prospective cohort study evaluated the usefulness of DD23 in bladder cytology specimens from
308 patients [48]. Of these specimens, 164 were
voided urine, 49 were catheterized urine, and 95
were bladder barbotage specimens. DD23 and cytol-
99
Summary
e) Quanticyt Nuclear Karyometry
Quanticyt analyses of bladder wash specimens
improve the rate of detection of high grade tumors
[282]. However, in that study, the risk score of the
first sample was not predictive of recurrence. It was
only after 5 samples that the rate of finding invasive
disease was 10% among individuals classified as
high-risk by Quanticyt [282]. However, a study by
Wiender et al. indicates that Quanticyt may overestimate the risk for bladder abnormalities, and, therefore, has a lower specificity than bladder wash cytology and voided urine cytology [281]. Some samples
may also be eliminated due to too few urothelial
cells, or if the sample has an abundance of leukocytes and erythrocytes.
1. INTRODUCTION
Summary
DD23 is a monoclonal antibody that detects a protein dimer expressed on bladder cancer cells. It is
meant to be used with urine cytology and is performed by one laboratory, Dianon (LabCorp).
This combination improves the detection of bladder cancer, especially low grade disease. The 90%
negative predictive value suggests that the combination of DD23 and cytology could be used to
decrease the frequency of cystoscopy. Prospective
validation of this concept is needed.
Quanticyt is an automated quantitative karyometric
cytology system that enables objective interpretation
of nuclear features (i.e., nuclear shape and DNA content) in light microscopy images. Based on the nuclear features, individuals are stratified in various risk
groups for bladder cancer.
Quanticyt nuclear karyometry measures mean
nuclear shape (MPASS) and DNA content (2c
deviation index or 2cDI) parameters and stratifies
patients into low-, intermediate-, or high-risk for
bladder cancer. The analysis requires sophisticated instrumentation, bladder wash specimens, and
technical expertise. In some cases, the test may
overestimate the risk for bladder cancer. At the
present time, general applicability of this marker
is limited.
2. METHODOLOGY
The test involves staining of a cytospin preparation
of ethanol-polyethylene glycol fixed bladder wash
specimens. The nuclear images observed under a
light microscope are transferred to a computerized
image analysis system. Samples are assessed for
mean nuclear shape (MPASS) and DNA content (2c
deviation index or 2cDI) parameters using an internal lymphocyte standard [4,160,278-280]. Based on
the Quanticyt results, the study individuals are identified as being at low-, intermediate-, or high-risk for
bladder cancer.
f) Multi-target Multi-color FISH Assay (UroVysion
Test)
1. INTRODUCTION
Cytogenetic studies reveal frequent alterations in
chromosomes 1, 3, 4, 7, 8, 9, 11, 17, etc., in urothelial cancers [283,284]. Recently, Junker et al., in a
retrospective study involving archival bladder cancer
specimens, evaluated the frequency of the loss of
heterozygosity (LOH) for various chromosomes.
The LOH was the highest for chromosome 9p
(54.9%), followed by 9q (49.3%), 13q (40.8%), 14q
(40.8%), 10q (39.4%), 17p (39.4%), 8p (38%), 21q
(36.6%), 11p (31%), 18q (23.9%), 4q (21.1%), 3p
(16.9%), 6q (14.1%), and 1q (8.1%). Deletion in
chromosome 9p21 at the p16 gene locus has been
identified as an early event in bladder cancer development [284]. Chromosomal abnormalities can be
detected by FISH. FISH assay involves binding (i.e.,
hybridization) of specific fluorescently-labeled DNA
probes to chromosome centromeres or unique loci on
the chromosomes that are altered in tumor cells. This
hybridization allows detection of cells with a fluorescence microscope and recording system. For
detecting bladder cancer cells, FISH assay is per-
3. RESULTS
In 2 studies, the Quanticyt test had 59% and 69%
sensitivity, respectively, for detecting bladder cancer,
while the specificity was 70% [280,281]. The test
had 57%, 56%, and 85% sensitivity to detect G1, G2,
and G3 bladder cancer, respectively. Witjes et al.
reported an 82.6% and 50% prognostic NPV and
PPV, respectively, for Quanticyt [160]. Van Rhijn et
al. found that among the 105 high-risk patients identified by Quanticyt, malignancy was found in 54
patients [279]. Furthermore, a 2cDI ≥ 2.00 was a significant predictor of CIS, invasive bladder cancer,
and progression. Thus, a 2cDI > 2.00 can be used to
further stratify patients with high-risk invasive bladder cancer [279]. Van der Poel et al., in a retrospective study of 614 patients and 5832 bladder wash
specimens, suggested that consecutive cytology and
100
formed on exfoliated cells. The sensitivity of a multicolored multi-probe with FISH assay is better than a
single probe.
some of which also compared the sensitivity of
UroVysion to other markers, the sensitivity of the
UroVysion test varied between 69% and 87% [47,5961,124,286]. These studies report a low sensitivity of
UroVysion to detect low grade (36%-57%) and low
stage (62%-65%) tumors [47, 60-61,124,287]. The
test has high sensitivity to detect high grade and high
stage tumors (83%-97%) and also to detect CIS
(about 100%) [47,59-61,124,286]. The specificity of
the UroVysion test reported in various studies is high
and varies between 89% and 96% [47,5961,124,286]. The test also has high specificity
among patients who have a variety of benign genitourinary conditions, including microhematuria,
benign prostatic hyperplasia, infections, and inflammation [47,124,288].
2. METHODOLOGY
UroVysion test is a multi-target multi-color FISH
assay that uses peri-centromeric fluorescent probes
for chromosomes 3, 7, and 17, and a locus specific
probe for the 9p21 region (P16 locus). The test
involves fixing of exfoliated cells from 10 to 50 mL
of urine specimens and placing them in wells of 12well slides. The cells are incubated with denatured
Chromosome Enumeration Probe (CEP) 3 (spectrum
red), CEP7 (spectrum green), CEP17 (spectrum
aqua), and Locus Specific Identifier (LSI) 9p21
(spectrum gold). The slides are counterstained and
observed under a fluorescence microscope (UroVysion/Abott Laboratories insert). The criteria for
detecting bladder cancer include finding 5 or more
urinary cells with gains of 2 or more chromosomes,
or 10 or more cells with gain of a single chromosome
(such as trisomy 7). Homozygous detection of 9p21
locus in greater than 20% of epithelial cells is considered a positive result [124,285]. However, currently there are no universally accepted criteria for
determining the positivity of a FISH test. For example, Friedrich et al. discarded specimens with less
than 100 cells/slide and considered a specimen as
positive if 20% of the cells gained 2 or more chromosomes or 40% of cells gained or lost one chromosome (i.e., 9p21 [59,60]. Skacel et al. considered a
specimen as positive if 5 or more cells gained 2 or
more chromosomes (3, 7, or 17) or 10% or more of
cells had trisomy of 1 of the chromosomes 3, 7, or 17
or 12 or more cells showed the loss of the 9p21 locus
[88]. Dalquen et al. discarded samples with less than
25 cells and considered a sample as positive if 3 or
more cells showed a gain of 3 or more copies of
chromosomes 3, 7, and 17 and a heterozygous or
homozygous loss of the 9p21 locus [286]. In addition, some studies have used only 2 of the 4 probes
provided in the UroVysion test to ascertain the presence of bladder cancer [287].
In some studies, the UroVysion test has been shown
to predict recurrence. For example, Skacel et al., in a
retrospective cohort study, reported that 8 of 9 FISHpositive patients with atypical cytology but negative
biopsy had biopsy-proven bladder cancer in 12
months [88]. Bubendorf et al., in a case-control study,
reported that 4 of the 5 false positive patients on the
UroVysion had a recurrence within 8 months; however, none of the true negative cases recurred within 18
months. It should be noted that the criteria used in the
Bubendorf study to detect abnormal cells were different from those suggested by the manufacturer [287].
Furthermore, Bubendorf et al. concluded that the
optimal criteria to define a FISH-positive result are
not absolutely clear and that not all FISH aberrations
are equally important [287]. Noting the high sensitivity of the UroVysion test to detect chromosomal
abnormalities, Veeramachaneni et al., in a cohort
study, concluded that a positive FISH test may indicate frank neoplastic urothelial transformation, or it
may merely be an indicator of unstable urothelium
capable of or primed for malignant transformation,
thus detecting patients at significant risk [290].
Summary
Based on case-control and cohort studies, the UroVysion test appears to be a promising test for
detecting bladder cancer. It may have an ability to
detect bladder tumor recurrence prior to its clinical
detection. However, it is important to develop a
consensus for the criteria used for the evaluation of
abnormal cells. The test also has low sensitivity to
detect low grade bladder tumors. Furthermore, at
this time, it is not clear whether a positive UroVysion indicates both the neoplastic transformation
(i.e., presence of bladder cancer) and an unstable
urothelium primed for malignant transformation.
3. RESULTS
In initial case-control cohort studies, the sensitivity
of the UroVysion test to detect bladder cancer was
81% to 84% [288,289]. These groups reported an
overall sensitivity of 81% and a specificity of 96%
for detecting bladder cancer. However, in those studies, the sensitivity of the UroVysion assay was low in
detecting low grade tumors (36%) and was not very
different from that of voided urine cytology (27%)
[289]. In recent case-control and cohort studies,
101
BTA-Stat and UBC were 70% and 90%, respectively.
VII. COMPARATIVE ANALYSIS OF
BLADDER TUMOR MARKERS
(2000-2004)
In the second study, when comparing the performances of the UBC-IRMA and the NMP-22 among
patients with symptoms suggestive of bladder cancer, Mian et al. used 10 U/mL cutoff for the NMP-22
test and 12 µg/L cutoff for the UBC-IRMA [186].
UBC-IRMA had a slightly higher sensitivity (64.8%)
than the NMP-22 (55.5%) in detecting bladder cancer. While the sensitivity of UBC-IRMA for detecting G1, G2, and G3 bladder tumors (66.6%, 60%,
and 68.7%) was very similar, the sensitivity of NMP22 was slightly higher for detecting G3 tumors (50%,
50%, and 68.7%). The specificities of NMP-22 and
UBC-IRMA were 79% and 92%, respectively. However, both tests had a higher positive rate among
patients with cystitis or benign lesions of the urinary
tract. Based on both studies, Mian et al. concluded
that although the UBC tests (Rapid and IRMA) are
superior to both the BTA-Stat and the NMP-22 tests,
all of these tests can be used only to lower the number of cystoscopies while monitoring recurrence, not
to replace it completely [183,186].
Several studies have compared sensitivity and specificity of a variety of markers with each other and
with cytology. Most of the markers have significantly higher sensitivity than cytology to detect bladder
cancer. The sensitivity of many markers also varies
with tumor grade, stage, and size. Depending upon
the population that is evaluated, some markers show
specificity comparable to cytology in side-by-side
comparison studies. Many markers show lower
specificity among patients with benign urologic conditions such as cystitis, urinary tract infection, hematuria, urolithiasis, and BPH. Table 4 summarizes
some of the comparative studies conducted between
2000 and 2004 that allow us to compare the performance of different markers evaluated in the same
study population.
Giannopoulas et al., in a cohort study of 213 patients,
compared the efficacies of the urinary UBC-IRMA,
NMP-22, and BTA-Stat tests [291]. The study population included new patients, as well as patients who
previously had superficial bladder cancer. For the
NMP-22 test, the authors’ used 8 U/mL as the cutoff
limit, which is lower than the cutoff limit suggested
by the manufacturer (10 U/mL). The cutoff value
used for UBC-IRMA was the same as that suggested
by the manufacturer. The overall sensitivity and
specificity were 72.9% and 64.6% for the BTA-Stat,
63.5% and 75% for NMP-22, and 80.5% and 80.2%
for the UBC test, respectively. The UBC test also
detected low grade and low stage bladder cancer
with higher sensitivity and specificity than NMP-22
and BTA-Stat. The sensitivities of BTA-Stat and
NMP-22 increased significantly with tumor grade,
but the sensitivity of UBC-IRMA increased only
marginally. Based on these results, the authors concluded that UBC might be a better diagnostic marker for bladder cancer than NMP-22 and BTA-Stat.
In a case-control retrospective study involving 112
symptomatic bladder cancer patients and 75 patients
with benign genitourinary conditions, Sánchez-Carbayo et al. compared the diagnostic potential of the
UBC-IRMA, NMP-22, and CYFRA 21-1 tests with
cytology and microhematuria [104]. In this study, the
authors also compared the diagnostic characteristics
of urinary tumor markers with or without normalization to urinary creatinine. In the absence of normalization, the UBC-IRMA, CYFRA 21-1, and NMP-22
tests had 69.4%, 67.3%, and 61.2% sensitivities and
91.3%, 88.4%, and 89.9% specificities, respectively.
Normalization to creatinine increased the sensitivity
of CYFRA 21-1 (75.5%) and NMP-22 (73.5%),
however, it decreased the specificity significantly
(NMP-22, 68.1% and CYFRA 21-1, 71%). The
increased sensitivity and decreased specificity could
also be due to the use of different cutoff limits when
the values of the markers were normalized to creatinine than when non-normalized values were used.
All 3 markers had significantly higher sensitivity
than cytology (35.4%) and microhematuria (55.1%).
However, the majority of the false negatives were
among patients with G1 tumors and superficial bladder cancer. The sensitivity of all 3 markers for detecting G1 tumors varied between 27% and 54%, regardless of whether the marker levels were normalized to
creatinine. The false positive rate for all 3 markers
among patients with benign genitourinary conditions
(such as BPH, urinary tract infection, stenosis, and
Mian et al. compared the accuracy of the UBC tests
(IRMA and Rapid) with BTA-Stat and NMP-22 in 2
separate retrospective cohort studies [183,186]. The
first study involved 183 patients, 57 suspected of
having bladder cancer and 123 with a history of bladder cancer. The BTA-Stat and UBC-Rapid tests had
52.8% and 66% sensitivities, respectively, for detecting bladder cancer [183]. The sensitivities of both
UBC-Rapid and BTA-Stat to detect low grade
tumors were low, at 38.8% for the BTA-Stat and
44.4% for UBC, respectively. The specificities of the
102
lithiasis) was between 23% and 39%, either with or
without normalization to urinary creatinine. Therefore, although the combination of the NMP-22,
UBC, and BTA-Stat tests will improve the sensitivity of bladder cancer detection, it will significantly
impact the specificity and the positive predictive
value of the combination.
Gutierrez-Banos et al. compared the efficacies of the
NMP-22, BTA-Stat, and cytology in a cohort of 150
symptomatic patients and patients with a history of
bladder cancer [292]. The sensitivities of NMP-22 at
6 U/mL and 10 U/mL were 84.2% and 76.3%,
respectively. The sensitivities of NMP-22 to detect
G1, G2, and G3 bladder tumors were 68.7%, 75.9%,
and 100%, respectively at 6 U/mL cutoff and 50%,
69%, and 96.8%, respectively, at 10 U/mL cutoff.
The sensitivities of the BTA-Stat and cytology for
detecting bladder cancer were 72.3% and 69.7%,
respectively. The sensitivities for detecting G1, G2,
and G3 tumors were 56.2%, 62.1%, and 90.3%,
respectively, for the BTA-Stat and 43.8%, 62.1%,
and 90.3%, respectively, for cytology. The specificities of the BTA-Stat (89.2%), NMP-22 (86.5%, 6
U/mL, and 90.5%, 10 U/mL), and cytology (93.2%)
were comparable. Based on these results, the authors
suggested using 6 U/mL as a cutoff for the NMP-22
test. However, this conclusion should not be generalized because, in the study by Boman et al., NMP-22
had low sensitivity (65% for detecting new tumors
and 45% for detecting recurrent tumors) even when
a cutoff value of 4 U/mL was used [135]. Since in the
Gutierrez-Banos study all tests including cytology
had higher sensitivity for detecting bladder cancer, it
is possible that the study patients might have had
larger tumors, which are more readily detected by the
markers.
In 2 case-control retrospective studies, Boman et al.
compared the performances of the BTA-Stat, NMP22, and UBC-IRMA with bladder wash cytology in
detecting new tumors and tumor recurrence among a
total of 250 study patients [55,135]. The cutoff limits for NMP-22 and UMC-IRMA in these 2 studies
were 4 U/mL and 1 ng/mL, respectively. The first
study documents that there is a large difference in
size between new tumors (median size 15 mm) and
recurrent tumor (median size 6.5 mm) and that new
tumors tend to have higher grade and stage than
recurrent tumors [135]. The sensitivity of all 3 markers for detecting new tumors was higher (NMP-22,
65%, BTA-Stat, 75% and UBC-IRMA, 60%) than
that for detecting recurrent tumors (NMP-22, 45%,
BTA-Stat, 55% and UBC-IRMA, 40%). The sensitivity of bladder wash cytology for detecting both
new and recurrent tumors was about 40%. The difference in the sensitivity of the 3 markers for detecting new and recurrent tumors disappeared when the
tumors in both categories were differentiated with
respect to size, grade, and stage. Thus, all 3 markers
had a lower sensitivity for detecting smaller superficial tumors. In the second study, Boman et al. compared the sensitivity of NMP-22, UBC-IRMA, flow
cytometry, and bladder wash cytology to detect different sizes of tumors (≤ 10 mm to ≥ 31 mm). Sensitivity of NMP-22 was about 75% among tumor sizes
≤ 10 mm to 21 to 30 mm, but it increased to 93%
when tumors were ≥ 31 mm. The sensitivity of BTAStat and UBC-IRMA increased from about 55% to
100% between tumor sizes ≤ 10 mm and ≥ 31 mm.
Interestingly, the sensitivity of bladder wash cytology also increased from 35% to 85% between tumor
sizes ≤ 10 mm and ≥ 31 mm. Based on these studies, the authors concluded that NMP-22, UBCIRMA, and BTA-Stat markers or any combination of
them cannot replace follow-up cystoscopy, mainly
because most recurrent tumors are small. Another
point to consider is that if the purpose of noninvasive
tumor markers is to detect bladder tumors before
they become invasive, the tumor markers should
have a reasonably high sensitivity for detecting
small, superficial tumors.
In a retrospective cohort study involving 94 new
patients suspected of having bladder cancer and 102
patients with a history of bladder cancer, Casetta et
al. compared the usefulness of the BTA-TRAK and
NMP-22 with urine cytology performed on 3 consecutive samples to detect bladder cancer. This is the
only study where the sensitivity of cytology was
higher than the tumor makers under study [293]. The
overall sensitivities of the NMP-22 (cutoff 11
U/mL), BTA-TRAK (cutoff 60 U/mL), and cytology
were 56%, 57%, and 59.3%, respectively. When
“dubious results” on cytology were considered as
positive cases, the sensitivity of cytology increased
to 73.3%. The sensitivity of the 2 tumor markers was
not different in the 2 groups, and it did not improve
by lowering the cutoff values on both tests. Based on
these results, the authors concluded that urine cytology performed on 3 samples outperforms the NMP22 and BTA-Stat tests. The authors also observed
that the diagnostic advantage of cytology over the 2
urine tests was maintained even when the patients
were stratified according to tumor grade.
103
Table 4. Comparative Studies of Tumor Markers
104
Table 4. Comparative Studies of Tumor Markers (Continued)
105
Table 4. Comparative Studies of Tumor Markers (Continued)
106
Table 4. Comparative Studies of Tumor Markers (Continued)
107
Table 4. Comparative Studies of Tumor Markers (Continued)
108
Table 4. Comparative Studies of Tumor Markers (Continued)
109
Table 4. Comparative Studies of Tumor Markers (Continued)
110
Table 4. Comparative Studies of Tumor Markers (Continued)
111
cluded that several variables including interlaboratory differences in sample storage and sample processing and the presence of occult blood may lead to
poor reproducibility of the TRAP assay and hTERT
RT-PCR. In this study, only patients with bladder
cancer were studied, and, hence, evaluation of specificity was not performed.
Serretta et al. compared the efficacy of the NMP-22,
BTA-Stat, and BTA-TRAK tests in a cohort study of
170 patients, who were being followed for recurrent
superficial bladder tumors [138]. The NMP-22,
BTA-Stat, and BTA-TRAK tests had sensitivities of
55%, 62%, and 79%, respectively, for detecting bladder cancer recurrence. In this study, approximately
52% of patients were receiving adjuvant intravesical
chemotherapy. All 3 tests showed higher false positive rates among these patients. This is not surprising, since during the course of chemotherapy there is
cell death (releasing NMP-22 in urine) as well as
inflammatory reaction (possibly causing the BTAStat and TRAK tests to be positive), which could
lead to positive NMP-22, BTA-Stat and BTA-TRAK
tests. The authors of this study concluded that bladder cancer monitoring using certain noninvasive
tests should not be carried out during intravesical
treatment.
In a case-control study involving 44 bladder cancer
patients and 26 age-matched controls with a wide
variety of clinical disorders, Cassel et al. evaluated
the performance of TRAP-ELISA and cytokeratin-20
RT-PCR to detect bladder cancer [193]. The clinical
disorders included BPH, perichondroitis, renal colic,
bilateral inguinal hernia, epilepsy, prostatectomy,
impotence, facialis, and bowel obstruction. In this
study, the telomerase activity and cytokeratin-20 RTPCR had 84.1% and 81.8% sensitivity, respectively,
for detecting bladder cancer. However, among the
urological and non-urological cases, the specificity
of telomerase activity (24.1%) and cytokeratin-20
(55.2%) was low. These results demonstrate that
telomerase activity and cytokeratin-20 expression
are not specific for malignancy and may be detected
in many benign cases. Therefore, the use of these
molecules as potential markers for bladder cancer
needs to be carefully evaluated.
As discussed in the earlier section, an RT-PCR assay
that amplifies the human telomerase reverse transcriptase (hTERT) may be a better alternative to the
TRAP assay for detecting bladder cancer. Bialkowska-Hobrzanska et al., in a prospective study involving a small number of bladder cancer patients (n =
35), directly compared the TRAP assay and
hTERT/GAPDH RT-PCR to detect bladder cancer in
a study of 35 patients [263]. In the hTERT/GAPDH
RT-PCR assay, the hTERT message amplification is
normalized to the amplification of GAPDH (a housekeeping gene), which eliminates disparity in results
due to different amounts of exfoliated cells in different samples, differences in RNA extraction, etc. In
this study the hTERT/GAPDH RT-PCR outperformed the TRAP assay by almost twofold, in terms
of sensitivity (94.3% for hTERT/GAPDH versus
48.6% for TRAP assay, P < 0.001). The TRAP assay
(43.8% and 52.6%) and hTERT (100% and 89.5%)
had similar sensitivities in detecting primary and
recurrent tumors. The sensitivity of urine cytology in
this study was 61.9%. The hTERT/GAPDH had a
significantly higher sensitivity (90%) in detecting
G1 and G2 tumors than the TRAP assay (25%) and
urine cytology (58.3%). The overall specificities of
the hTERT/GAPDH RT-PCR (92%), TRAP assay
(100%), and urine cytology (100%) were comparable. Thus, in this small study, the hTERT/GAPDH
RT-PCR was significantly better than the TRAP
assay for detecting bladder cancer.
Halling et al., in a case-control study of 265 individuals which included 146 patients with a history of
bladder cancer and 119 benign genitourinary conditions, compared the sensitivity and specificity of
BTA-Stat, UroVysion, hemoglobin dipstick testing,
and the telomerase TRAP assay. The sensitivities of
UroVysion (81%), BTA-Stat (78%), and hemoglobin
dipstick (74%) were similar but that of telomerase
was low (36%). The sensitivity of all tests to detect
G1 tumor was low and ranged between 30% and
50%; UroVysion had 36% sensitivity to detect G1
tumors. Except for telomerase, the sensitivity of the
other 3 tests increased with both tumor grade and
stage. The specificity of UroVysion was the highest
(96%), followed by telomerase (91%), BTA-Stat
(74%), and hemoglobin dipstick (51%). Based on
these studies, the authors concluded that the UroVysion test is a promising new marker for the detection
of bladder cancer [124].
In a case-control prospective multi-center study
involving 176 patients with a history of bladder cancer and 265 control individuals (both healthy individuals and patients with non-bladder cancer conditions), Sarosdy et al. compared the performance of
BTA-Stat, UroVysion, and voided urine cytology
[47]. In contrast to the study by Halling et al., the
UroVysion test had significantly higher sensitivity
In contrast to the Bialkowska-Hobrzanska study, de
Kok et al. found that the sensitivity of the TRAP
assay (29%) and hTERT real-time (i.e., quantitative)
RT-PCR (24%) was poor [261]. The authors con-
112
(71%) than BTA-Stat (50%), with cytology having
26% sensitivity. The specificity of only UroVysion
test was reported in this study and was very high
(94.6%). Consistent with earlier reports, UroVysion
(55%), BTA-Stat (27%), and cytology (18%) had
low sensitivities to detect low grade tumors. However, the sensitivity of BTA-Stat and UroVysion
increased with tumor grade and stage. In BCG-treated patients, the sensitivities of both UroVysion
(55%) and BTA-Stat (41%) were lower than cytology (60%). The specificity of UroVysion in BCGtreated patients (89%) was not only higher than
BTA-Stat (75%), but was also higher than cytology
(71%). Based on these studies, Sarosdy et al. concluded that the sensitivity of UroVysion is at least
comparable to BTA-Stat and has specificity comparable to cytology.
ic, and that the UroVysion test has low sensitivity to
detect low grade tumors.
Lokeshwar et al. compared the performance of the
HA-HAase test with the BTA-Stat in 26 patients with
a history of bladder cancer, which were followed
over a 4-year period (111 urine specimens). [38]
These patients were monitored over a course of 4
years. The HA-HAase and BTA-Stat tests had 94%
and 61% sensitivity, 63% and 74% specificity, and
87% and 64% accuracy, respectively. The HAHAase and the BTA-Stat tests had 89% and 88%
PPV and 77% and 38% NPV for detecting bladder
cancer. The HA-HAase test had 91%, 100%, and
92.3% sensitivity for detecting G1, G2, and G3 bladder tumors, respectively. The BTA-Stat test showed
73%, 52%, and 62% sensitivity for detecting G1, G2,
and G3 bladder tumors. In this study, 60% of the
false positive cases on the HA-HAase test recurred
within 4.7 months. However, during the same time
period, only 12% of the true negative cases recurred.
Thus, a false positive HA-HAase test carried a tenfold risk of recurrence within 4.7 months (risk ratio
= 10.2; OR = 24; P = 0.004). In contrast, a false positive BTA-Stat test did not carry any significant risk
of recurrence within 4.7 months (risk ratio = 1.4, OR
= 1.5; P = 0.756). This study concluded that the HAHAase test is superior to the BTA-Stat in monitoring
and predicting future bladder cancer recurrence. In
the same study, a comparison between the performance of the HA-HAase and BTA-Stat tests was
conducted for screening of 401 former Department
of Energy workers who had a possible exposure to
bladder carcinogens for at least 1 year. The HAHAase and BTA-Stat tests were positive among 14%
and 17% of the individuals, respectively. Sixty-three
percent of the positives on the BTA-Stat compared to
only 25% of the positives on the HA-HAase test had
abnormal urinalyses or benign urologic conditions. It
should be noted that even after a rigorous follow-up,
only 29 individuals positive on either 1 or both HAHAase and BTA-Stat tests underwent cystoscopy
and only 20, who were negative for bladder cancer,
reported back the results. This study suggests that
noninvasive tests with low false positive rates could
be used for bladder cancer screening. But, more
importantly, it also reveals some of the challenges in
terms of patient follow-up when conducting screening trials involving biomarkers.
Friedrich et al. and Toma et al. compared the sensitivity and specificity of Lewis X antigen and
486p3/12 markers with BTA-Stat, NMP-22, UroVysion, and Immunocyt [59,60]. In both studies, the criteria to detect a positive UroVysion test were different from those reported in studies by Halling et al.
and Sarosdy et al. [47,60]. In a cohort of 103 patients
which included 55 first time patients suspected of
having bladder cancer and 48 patients with a history
of bladder cancer, Friedrich et al. found that the sensitivity of Lewis X Ag was the highest (96%), followed by NMP-22/486p3/12 (both at 69%), UroVysion (68%), and BTA-Stat (67%). However, Lewis X
Ag had the lowest specificity. The specificity of
UroVysion was the highest (89%), followed by BTAStat (78%), 486p3/12 (76%), NMP-22 (65%), and
Lewis X Ag (33%). The sensitivities of all markers
increased with tumor grade and stage, particularly in
BTA-Stat, NMP-22, and UroVysion. Toma et al. conducted a cohort study involving 126 patients among
whom there were 47 patients suspected of bladder
cancer and 79 patients with a history of bladder cancer. For the Immunocyt test, 1 or more cells with red
and/or green fluorescence was taken as a positive
inference. The sensitivity of Lewis X Ag was the
highest (95.5%), followed by cytology (84.6%),
Immunocyt (78.3%), UroVysion (68.8%), 486p3/12
(68.6%), NMP-22 (68.5%), and BTA-Stat (66.6%).
As observed in the study by Friedrich et al., the
specificity of UroVysion was the highest (89.1%),
followed by cytology (80%), BTA-Stat (78.2%),
486p3/12 (76.4%), Immunocyt (73.8%), NMP-22
(65.2%), and Lewis X Ag (32.8%) [15]. Except for
Lewis X Ag, the sensitivity of all markers including
cytology increased with tumor grade. These studies
show that, although Lewis X Ag is a sensitive marker for detecting bladder cancer, it is not very specif-
Schroeder et al. compared the accuracy of HAHAase, BTA-Stat, UBC-Rapid, hemoglobin dipstick, and cytology to detect bladder cancer in a retrospective cohort study involving 138 urine specimens from 115 patients suspected of bladder cancer
113
tially detect high grade tumors [198,199]. This may
be the reason why the combination of the HA test
with either UroVysion or HAase test has higher sensitivity than the individual tests alone.
[58]. The sensitivity of the HA-HAase test (88.1%)
was the highest followed by cytology (70.6%), BTAStat (52.5%), hemoglobin dipstick (50.8%), and
UBC-Rapid (35.6%). The specificities of all markers
were comparable: HA-HAase/cytology was 81%,
hemoglobin dipstick 78.2%, BTA-Stat 76.7%, and
UBC-Rapid 75%. The sensitivities of all markers
increased with tumor grade; the most striking
increase was observed for BTA-Stat (G1, 25%; G2,
46.1%; and G3, 73.9%). The sensitivity of BTA-Stat
also increased with tumor stage. Based on these
results, the authors concluded that the HA-HAase
test is superior to cytology, BTA-Stat, hemoglobin
dipstick, and UBC-Rapid for detecting bladder cancer.
Van Rhijn et al. compared the efficacy of microsatellite DNA testing with the BTA-Stat and voided urine
cytology in 93 patients [56]. The microsatellite DNA
analysis, BTA-Stat, and cytology had 74%, 56%, and
22% sensitivities and 82%, 79%, and 95% specificities, respectively. In this study, data on the comparative analyses of the sensitivity of microsatellite DNA
analysis, BTA-Stat, and cytology according to tumor
grade and stage were not presented. However,
microsatellite DNA analysis missed all 11 TaG1
tumors. Interestingly, 55% of the false positive cases
on the microsatellite DNA test recurred within 6
months. In contrast, only 11.6% of the true negative
cases recurred during that time. Thus, the corrected
specificity of the test is 94%. It should be noted,
however, that 14 patients were eliminated from the
study either due to insufficient DNA quality or abundance of leukocytes, both of which render the results
of microsatellite testing unreliable. Based on these
results, the authors concluded that microsatellite
analysis, a DNA test in urine, reliably signals the
presence of recurrent bladder cancer, sometimes
even before cystoscopic evidence of disease.
Hautmann et al., in a retrospective cohort study
involving 94 consecutive patients, compared the
accuracies of cytology, Immunocyt, and the HAHAase test. The prevalence of bladder cancer in this
study was 31%, and it included mostly patients with
recurrence. The sensitivity of the HA-HAase urine
test (83.3%) was significantly higher than Immunocyt (63.3%) and cytology (73%). Among patients
without bladder cancer, the majority were patients
with a history of bladder cancer, and the specificities
of all of the 3 markers were comparable (HA-HAase
test, 78.1%; Immunocyt, 75%; and cytology, 79.7%)
[64].
Summary
Srougi et al. compared the accuracy of the HA test
(hyaluronic acid detection test part of the HA-HAase
test), UroVysion, BTA-Stat, and cytology in a
prospective study involving bladder cancer patients
with either primary or recurrent tumors [209]. The
specificity of these tests was determined in patients
with a history of bladder cancer but no evidence at
the time of testing and patients with benign prostatic
hyperplasia. The sensitivity of the HA test was the
highest (83%), followed by BTA-Stat (75%), UroVysion (73%), and cytology (67%). The specificity of
all of the tests was comparable among patients with
a history of bladder cancer and benign prostatic
hyperplasia: 86% versus 79% for HA, 82% versus
76% for UroVysion, 70% versus 72% for BTA-Stat,
and 74% versus 74% for cytology. The combination
of the HA test and UroVysion test had the highest
sensitivity at 95%. This is interesting since the combination of the HA test with the HAase test (HAHAase test) also has greater than 90% sensitivity
[198,199]. This study found that the UroVysion test
has high sensitivity to detect high grade tumors
(94%). The HAase test has been shown to preferen-
Comparative studies show that noninvasive tests
are more sensitive than cytology. Some of these
tests can also detect bladder cancer recurrence
before it can be detected clinically. Thus, noninvasive tests with a high sensitivity and reasonable
specificity can be used in a surveillance setting to
reduce the number of cystoscopies performed
each year for monitoring bladder tumor recurrence.
A few studies have evaluated the usefulness of
bladder tumor markers in a screening setting. The
use of noninvasive tests for screening a high-risk
population could be made economically sound by
choosing noninvasive tests that have high specificity and reasonable sensitivity. Furthermore,
concurrently performing urinalyses on each specimen and having knowledge about patients’ clinical histories might reveal conditions that could
render a false positive result on the noninvasive
tests.
114
1. CHROMOSOMAL ALTERATIONS AND ALLELIC DELETION (LOSS OF HETEROZYGOSITY)
VIII. PROGNOSTIC MARKERS FOR
BLADDER CANCER
• DNA and FISH Analysis
Recent advances in molecular genetic methodologies, such as loss of heterozygosity (LOH) analysis,
FISH analysis, and comparative genomic hybridization, have made it possible to identify the loss of several potential tumor suppressor genes in bladder cancer. Pycha et al. examined chromosome 7, 9, and 17
alterations using FISH, and p53 positivity in 190
muscle-invasive bladder cancer cases (94 urothelial
carcinomas and 96 squamous cell carcinomas).
Although numerical chromosomal alterations were
associated with progression-free survival, the alterations were not independent prognostic factors for
disease progression [295]. LOH studies have shown
that the loss of 17p, 3p, 13q, 18q, or 10q is found
more frequently in high grade, high stage bladder
cancer [283]. However, no large prospective study
has demonstrated that this type of genetic analysis
has prognostic value in patients with bladder cancer.
The complicated laboratory process required in this
type of analysis has hampered wide application in
clinical settings and a large scale study to date.
(Including markers for predicting recurrence, progression, disease-specific survival, and response to
chemotherapy and radiotherapy).
The current clinical and pathological parameters,
such as tumor grade, stage, and vascular and lymphatic extension, provide important prognostic information, yet still have limited ability to predict tumor
recurrence, progression, development of metastases,
and response to therapy or survival. A substantial
number of potential molecular markers for the prediction of clinical course and outcome have been
identified by recent studies of molecular biology and
genetics. However, no single marker is reliable
enough to predict the clinical course and outcome of
bladder cancers and to replace standard clinical and
pathological parameters.
For new candidate prognostic markers or tests to be
of clinical use, they must add some predictive capacity beyond what standard clinical and pathologic
parameters offer. To achieve this goal, at the least,
using sufficient numbers of subjects in the relevant
staging and grading categories, a multivariate analysis to determine each marker’s prognostic independence is required [294]. It is noteworthy that the
same criteria that apply to an ideal tumor also apply
to prognostic markers. However, at the present time
none of the prognostic markers have been tested as
rigourously as have been many of the diagnostic
urine markers. In particular, few prospective trials
have been conducted to test the performance of
potential prognostic markers in side-by-side comparisons. Unlike definitive strategies that are in place
for the development of diagnostic markers for bladder cancer, there is a lack of strategies for the development of prognostic markers. The performance of a
prognostic marker may also be complicated due to
the impact of therapy on the course of the disease.
These probably are some of the reasons why prognostic markers have not been implemented in the
management of patients with bladder cancer.
2. ONCOGENES
a) EGFR (Epidermal Growth Factor Receptor)
Several investigators have shown a positive association between overexpression of EGFR and high
grade, high stage bladder cancer, indicating that
EGFR expression identified by IHC (immunohistochemistry) is an independent prognostic factor in
patients with advanced bladder cancer [296-299].
Furthermore, the prospective evaluation of 212
patients with newly diagnosed bladder cancer confirmed EGFR expression as an independent predictor
of survival and stage progression [300]. In contrast,
although the EGFR expression by IHC was one of
the significant predictors of progression in patients
with Ta or T1 bladder tumors by univariate analysis,
it was not a significant predictor by multivariate
analysis [301]. Furthermore, EGFR expression by
IHC was seen in 86% of 43 invasive bladder cancer
cases treated by cystectomy and had no prognostic
significance [302].
In this section, representative bladder cancer prognostic markers are presented, and the relevant literatures focusing on prognostic significance are summarized, while extensive description of the biological role of each marker is omitted.
b) HER-2
The product of the HER-2/neu (c-erb-B2) oncogene
was found to be expressed frequently in urinary bladder carcinoma [303], and overexpression of HER-2
115
protein was shown to correlate with increased tumor
grade, cancer-specific survival, and incidence of
metastatic disease, and was an independent prognostic factor in a retrospective IHC study of 88 patients
with muscle-invasive bladder cancer [304]. Kruger
et al. also reported that HER-2 product was a significant and independent prognostic factor of tumorspecific survival in patients with muscle-invasive
bladder cancer by multivariate analysis [305]. Other
authors, however, found, in evaluations of 95 and 89
patients [306,307], that determination of HER-2 by
IHC provided no additional prognostic information
over tumor stage and grade for bladder cancer. In an
IHC study of 80 cases of muscle-invasive bladder
cancer treated by radical cystectomy, there was no
significant difference in the median survival between
HER-2-negative patients and HER-2-positive
patients (P = 0.46) [308]. In addition, they showed
no significant difference in the median survival
between patients with HER-2-negative lymph nodes
and those with HER-2-positive lymph nodes (P =
0.39) [308]. Therefore, it was claimed that HER-2
overexpression did not predict survival when analyzed by its presence either in the primary tumor or
in the regional lymph node metastasis [308].
ciated with disease progression and upstaging of the
tumor during radiation therapy [23]. However, bcl-2
overexpression had no significant effect on response
to a combination of platinum-based chemotherapy
and radiation therapy [315,316]. In patients treated
with TUR, bcl-2 expression did not offer any prognostic information in predicting either recurrence or
progression over conventional prognostic factors
[317].
e) MDM-2
Although amplification of the mdm-2 gene is infrequently seen in bladder cancer [318], mdm-2 overexpression by IHC has been reported in 20% to 30%
of bladder tumors (n = 87) [319]. However, the prognostic value of mdm-2 overexpression remains
unknown.
f) FGFR3
Molecular genetic analyses have shown the frequent
presence of FGFR3 point mutation in bladder cancers, especially in those with a low grade and stage
phenotype [320,321]. The presence of FGFR3 mutation might be a prognostic variable [30]. However,
no large study to determine whether FGFR3 mutation has significant prognostic independence is available at present.
In summary, the level of expression and the prognostic significance of HER-2 protein in urothelial
cancer varies among different studies, with some
revealing no prognostic relevance and others suggesting a better or worse prognosis [309].
g) c-myc
Although c-myc overexpression has been reported
more frequently in high grade tumors, no correlation
with recurrence, progression, or survival has been
demonstrated [323-325].
c) H-Ras
Mutations in the H-Ras gene at codons 12 and 61
have been implicated in the development and progression in up to 10% of bladder cancers [310].
However, no study has shown any prognostic value
in the presence of mutation. A potential prognostic
role of cH-Ras protein overexpression in cancer
patients has been suggested by Fontana et al., in
which the overexpression was correlated with early
recurrence in patients with superficial Ta or T1 bladder cancer [311]. However, this prognostic effect
was not clearly shown in other studies, and contradictory results have been observed as well [312,
313].
3. TUMOR SUPPRESSOR GENES
a) p53
The tumor suppressor p53 plays a key role in regulating cell cycle progression and apoptosis under
genotoxic conditions. The p53 gene mutations are
the most common genetic defect in human cancers
[326]. Mutated p53 protein often results in a prolonged half-life compared to the wild-type p53 and
accumulates in the cell nuclei; it can be detected by
IHC. The comparison of p53 detection by IHC and
molecular analysis, including the PCR-SSCP method
and DNA sequencing, has shown that p53 accumulation correlates with the mutated p53 gene [327].
However, there may be a considerable number of
discordant cases of p53 gene mutation confirmed by
DNA sequencing and “altered p53” judged by IHC
[328]. Owing to the complicated process of molecular analysis, many groups have investigated the prognostic value of p53 by IHC. However, a recent study
d) Bcl-2
Shiina et al. found no significant correlation between
bcl-2 expression by IHC and overall survival in 77
patients who received cystectomy [314]. In an analysis of 109 patients with invasive bladder carcinoma
treated with preoperative radiation therapy without
concurrent chemotherapy, Pollack et al. demonstrated that bcl-2 overexpression was significantly asso-
116
of the Bladder Cancer Marker Network showed that,
although there was a high degree of agreement for
negative p53 expression or strongly p53-positive
samples, a high level of variability between laboratories and observers existed in the gray zone of low
p53 positivity between 1% and 20% [294]. Taken
together, one should be cautious in interpreting a
large amount of literature concerning the association
between p53 expression by IHC and clinical outcome.
positivity was one of the independent cancer-related
survival variables [336]. In 102 high-risk patients
with Tis to T1 tumors treated with BCG, p53 overexpression was shown to be an independent predictor of recurrence [337]. Furthermore, in a study
including 198 Tis to T1 patients who received adjuvant or therapeutic BCG therapy, p53 positivity after
BCG therapy was the only independent marker of
disease progression in a subgroup of patients with
residual disease after BCG therapy [338].
1. P53 AS A MARKER IN PATIENTS WITH MUSCLEINVASIVE BLADDER CANCER
While the above-mentioned studies have demonstrated a significant predictive value in p53 expression in patients with Tis to T1 bladder cancer, there
are several studies that indicate absence of such predictive value. Peyromaure et al. reported that p53
positivity had no predictive value for recurrence and
progression in 29 patients with T1G3 tumors treated
with TUR followed by intravesical BCG [339]. The
role of p53 positivity as an independent predictive
marker in patients with BCG-treated superficial
bladder cancer was also denied in another study
[340]. In a study of 93 patients with G1 or G2, Ta to
T1 bladder cancer, the Ki-67 labeling index, but not
p53 positivity or Bcl-2 overexpression, was the only
significant prognostic indicator for recurrence in univariate and multivariate analyses [341]. The absence
of a role of p53 positivity as an independent prognostic variable for recurrence or progression in Ta or
T1 bladder cancer has been reported in several studies [342-344].
One large study of 253 patients treated by radical
cystectomy indicated that p53 positivity in the nucleus by IHC was an independent predictor of recurrence and overall survival in a multivariable analysis
stratified according to grade, pathologic stage, and
lymph node status [329]. However, in a cohort of 59
patients with pathologically confirmed lymph nodepositive bladder cancer treated with cystectomy, p53
positivity was not predictive of disease-free survival
in node-positive disease [330]. In a study of 212
bladder cancer patients, a multivariate survival analysis indicated p53 positivity had no independent
prognostic value over clinical stage and mitotic
index [331]. The Bladder Cancer Marker Network
also evaluated a series of 109 patients with G2 or G3,
T2 to T3 disease and found no prognostic value of
p53 staining [332]. In a study of 109 patients with
pT2N0M0 bilharzial-related bladder cancer, p53,
along with MIB-1(Ki-67), Bcl-x, and BAX, was an
independent predictor for progression-free survival
in urothelial carcinoma group (n = 49), and p53 positivity and PCNA were independent predictors in the
squamous cell carcinoma group (n = 60) [333].
Among the contradictory results of many studies of
p53 status as a prognostic variable in muscle-invasive bladder cancer, Schmitz-Dräger et al. reviewed
all published literature on the association of p53 positivity and prognosis of bladder cancer patients in a
recent meta-analysis [334]. In only 2 out of the 7 trials in muscle-invasive bladder cancer was p53
regarded as an independent prognostic marker of disease progression [42].
2. P53 AS A PROGNOSTIC MARKER
TIS TO T1 BLADDER CANCER
IN
The role of p53 positivity as an independent prognostic marker in Tis or T1 bladder cancer patients
with or without BCG treatment has not been clearly
demonstrated at present.? However, a meta-analysis
by Schmitz-Dräger et al. showed about a 50% rate of
positive multivariate analyses of p53 positivity as a
prognostic marker of progression in T1 bladder cancer [334].
3. P53 AS A RESPONSE MARKER TO CHEMOTHERAPY OR
RADIOTHERAPY
A study in 111 patients with invasive bladder cancer
treated with neoadjuvant MVAC therapy suggested
that p53-positive tumors have a lower response to
chemotherapy [345]. In support of this finding,
Kakehi et al. reported that p53-negative tumors
responded favorably to cisplatin-based combination
chemotherapy in a cohort of 60 muscle-invasive or
metastatic bladder cancer patients [346].
PATIENTS WITH
In a study including 43 patients with T1 bladder cancer, patients having tumors with 20% or more tumor
cells with p53 positivity had a significantly lower
progression-free interval [335], and this finding was
supported by several other studies. In a more recent
study of 175 patients with T1 bladder cancer, p53
In another study of 60 patients treated with cisplatinbased systemic chemotherapy for locally advanced
and/or metastatic urothelial cancer, p53 negativity
117
was correlated with complete or partial remission
following inductive chemotherapy, indicating that
tumors with intact p53 responded significantly better
[347]. In contrast, one preliminary study showed that
p53-positive tumors responded better to adjuvant
chemotherapy in patients treated by radical cystectomy [348]. In 50 primary bladder cancers with
metastatic lesions, p53 positivity was not correlated
with response to cisplatin-based chemotherapy or
surviva [349].
and survival [353]. In another study examining p53
and Rb expression in 59 Ta or T1 bladder cancers,
there was more marked increase in progression (P =
0.00005) and decreased overall survival (P = 0.0004)
in patients having tumors with alterations in both,
after controlling for tumor stage, tumor grade, and
suspicion of vascular invasion [354]. These studies
suggest an independent yet synergistic role for p53
and Rb expression in the progression of bladder cancer.
Despite the lack of consistent published results with
regard to p53 status and response to chemotherapy,
appropriate studies using p53 with or without other
markers may be particularly helpful in treatment
decisions as they relate to using neoadjuvant and
adjuvant chemotherapy. One large prospective study
is currently enrolling patients with p53-positive
organ-confined bladder cancer treated by radical cystectomy with randomization to chemotherapy or
observation.
More recently, Chatterjee et al. examined p53, p21,
and pRb expression in 154 patients with high grade
superficial or muscle-invasive bladder cancers, and
reported that the number of altered markers (p53,
p21, and pRB) were significantly associated with
time to recurrence and overall survival by multivariate analysis [355]. In another study examining p53,
p21, pRB, and p16 expression in bladder cancers in
80 patients who underwent radical cystectomy, the
incremental number of altered markers was independently associated with an increased risk of bladder
cancer progression and mortality [356].
In a study of 109 patients treated preoperatively with
50 Gy radiation therapy followed by radical cystectomy, p53 positivity was not correlated with radiation response or overall survival. Ogura et al. also
showed no significant correlation between p53 positivity and radiosensitivity in 60 patients with muscleinvasive bladder cancer [350]. In another study of
131 patients with T2 to T4 bladder cancer treated
with external full-dose radiotherapy, multivariate
analysis indicated that the T category (T2 or T3 vs.
T4), histological grade, and p21 expression, but not
p53 positivity, were independent prognostic factors
for overall survival [351]. The lack of association
between p53 positivity and response to radiation
therapy was also found in 2 other studies [315,352].
The results of these studies show the lack of prognostic value of p53 expression with respect to radiation response in bladder cancer.
4. COMBINATION
MARKERS
OF P53 AND
Although these studies are retrospective and relatively small in number of subjects, these results indicate
that the analysis of the interaction of different cell
cycle regulatory proteins in combination with p53
will further increase the benefit of p53 determination
as a prognostic marker.
b) Rb
In a small cohort of 38 patients with muscle-invasive
tumors, Cordon-Cardo et al. reported that overall
survival, independent of stage, was higher in patients
with pRb-normal tumors than in those with pRbaltered (negative or weak) tumors [357]. Logothetis
et al. also reported a significantly poorer tumor-free
survival rate in those who had a tumor with an
altered Rb protein in 43 patients with locallyadvanced bladder cancer treated by surgery and
chemotherapy [358]. In an IHC study of 45 patients
with T1 bladder tumors, loss of Rb protein expression combined with altered p53 expression was associated with significantly poorer progression-free survival [359].
OTHER POTENTIAL
Because of the significance of p53 alterations in high
grade and advanced bladder cancers, the significance
of p53 expression combined with other potential
markers was explored in several studies. Cote et al.
examined p53 and Rb protein expression by IHC in
bladder cancers from 185 patients who underwent
radical cystectomy, and reported that patients having
tumors with both p53 and Rb alterations had significantly increased rates of recurrence (P < 0.0001) and
survival (P < 0.0001) compared to those with no
alterations, and patients with alterations in only 1 of
these proteins had intermediate rates of recurrence
4. CELL CYCLE REGULATORS
a) p21
In an IHC study for p21 and p53 expression in 242
patients who underwent cystectomy, multivariate
analysis showed that p21 IHC labeling was an independent predictor of tumor recurrence and survival
[68]. Furthermore, patients with p53-altered/p21-
118
negative tumors demonstrated a higher rate of recurrence and worse survival compared with those with
p53-altered/p21-positive tumors [360]. In 96 patients
with superficial urothelial carcinoma, multivariate
analysis indicated that negative p21 expression was
an independent predictor of reduced overall survival,
but not of disease-free survival [361]. In contrast,
Lipponen et al. reported that low p21 positivity was
associated with a better prognosis for Ta and T1
tumors (n = 186), although not significantly [362]. In
a multicenter study of 207 patients with superficial
(Ta or T1) bladder cancer, p21 expression by IHC
provided no additional prognostic information compared with established prognostic factors for predicting the risk of tumor recurrence and progressive disease [363]. Furthermore, high p21 expression
(>10%) was associated with shorter recurrence-free
intervals in 47 patients with superficial bladder cancer who were treated with 6 weekly intravesical
BCG instillations [363]. Therefore, to date, the role
of p21 expression as a prognostic variable remains
controversial and unknown.
variate analysis. In 159 patients with Ta or T1 bladder cancer, a high Ki-67 index (≥18%) and multifocality were significantly related to recurrence and
progression-free survival and were independent
prognostic factors in the multivariate analysis [368].
In a study examining the prognostic value of MIB-1
score, p53, EGFR, mitotic index, and papillary status
in 207 patients with Ta or T1 bladder cancer, only
MIB-1 score and papillary status were independent
predictors of progressive disease- and cancer-specific survival by multivariate analysis [369].
Stavropoulos et al. evaluated p53, bcl-2, and Ki-67
expression in 58 Ta or T1 patients, and found that the
Ki-67 index was the only independent prognostic
factor for recurrence in patients treated with TUR
alone [370]. A study in 114 bladder cancer patients
showed that Ki-67 expression, as well as tumor stage
and p53 positivity, provides independent prognostic
information in relation to progression-free and disease-specific survival in multivariate analysis [371].
In a cohort of 192 patients with apparently superficial Ta or T1 urothelial carcinoma, only Ki-67 and
multifocality were found to be independent prognostic factors of recurrence in multivariate analysis,
whereas p53 positivity was not significant [342]. In
an analysis of 319 patients, Ki-67 index was an independent prognostic variable of recurrence of large
pTa or T1 tumors [343]. Furthermore, in a study
examining Ki-67, bcl-2, and p53 expression in 93
cases of primary, low grade, superficial bladder cancer, the Ki-67 labeling index was the only significant
prognostic indicator in predicting tumor recurrence
in univariate and multivariate analysis [341].
b) p27
In 120 consecutive cases of urothelial carcinoma,
p27 levels were significantly higher in low grade,
superficial, papillary, and slowly-proliferating
tumors [364]. Decreased p27 expression was associated with poor overall and post-relapse survival, and
the Ki-67/p27 status had the strongest bearing on the
overall survival of patients with muscle-invasive
tumors in a multivariate analysis [72]. In a series of
96 patients with superficial (pTa or T1) bladder cancer, low p27 expression by IHC was significantly
correlated with decreased disease-free survival (P =
0.0003 by log-rank test) and overall survival and was
an independent predictor of reduced disease-free survival, second only to tumor stage [365]. In 145 consecutive bladder cancer patients, low IHC p27
expression levels were independent predictors of
shortened disease-free and overall survival in multivariate analysis [366]. Furthermore, significant correlations were found between low IHC p27 expression and early recurrence in 86 patients with superficial disease (Ta or T1) [366].
These documents rather consistently indicate that
Ki-67 expression is a promising marker for recurrence and progression in superficial bladder cancer.
Larger prospective studies with a standardized
method and positive criteria, especially of the cutoff
value of the labeling index, may be warranted. In
addition, Ki-67 expression as a prognostic marker in
patients with locally-advanced or metastatic bladder
cancer remains unconfirmed.
d) Cyclin D1 and E
Although cyclin D1 is a positive regulator of the cell
cycle, Sgambato et al. reported that patients with Ta
or T1 tumors with low cyclin D1 expression, along
with low p27 and high Ki-67 expression, had
extremely high rates of recurrence [372]. In an IHC
study of 392 bladder specimens, cyclin D1 positivity
was not linked to a risk of recurrence or tumor progression, in patients with either pTa or pT1 tumors
[373]. In a multicenter IHC study of 207 patients
with superficial (Ta or T1) bladder cancer, the cyclin
c) Ki-67 (MIB-1)
The Ki-67 antigen detected by IHC, using the monoclonal antibodies Ki-67 and MIB-1, accumulates in
the nuclei of proliferating cells from the G1 phase to
mitosis, but not in the nuclei of quiescent or resting
cells [367]. There are a large number of studies that
define Ki-67 as an independent prognostic marker of
bladder cancer progression and recurrence in multi-
119
local invasion, lymphovascular invasion, and recurrence [379]. However, its expression was not an
independent prognostic marker for survival [379].
An IHC study including 39 patients with CIS and 34
with stage T1 tumors showed that COX-2 expression
was not associated with clinical outcome in the T1
patients [380]. In the CIS patients, COX-2 expression was significantly associated with disease recurrence using cutoffs of 0% and greater than 10% positive cells and with disease progression using a
greater than 20% cutoff [88]. In another small study
of 37 patients with initial T1G3 bladder cancer, who
had undergone complete TUR followed by 6 weeks
of intravesical instillation of BCG, COX-2 expression was a statistically significant variable in predicting both recurrence and disease progression
[381].
D1 expression level was an independent predictor of
tumor recurrence, but provided no additional prognostic information for predicting the risk of progressive disease [363].
A study using a tissue microarray of 2317 specimens
from 1842 patients with bladder cancer, staged Ta
through T3, demonstrated that low cyclin E expression was associated with poor overall survival in all
patients, but had no prognostic impact independent
of stage [82]. In a cohort of 145 consecutive bladder
cancer patients, low cyclin E expression was one of
the independent predictors of overall survival [366].
5. ANGIOGENESIS-RELATED FACTORS
Although numerous angiogenic factors have been
described, the relative importance of individual
angiogenic factors in the majority of tumor types
remains largely unclear.
6. EXTRACELLULAR MATRIX, ADHESION
MOLECULES, CELL SURFACE MARKERS,
AND RELATED PROTEINS
a) VEGF
Vascular endothelial growth factor (VEGF) is present in higher concentrations in the urine of patients
with bladder cancer than in that of controls, and urinary VEGF levels as determined by ELISA are correlated with tumor recurrence rates in patients with
Ta and T1 disease [375]. On the other hand, in a
study of 185 patients with pTa or T1 tumors, VEGF
expression by IHC was not correlated with a risk of
tumor recurrence or with patient survival [376].
Inoue et al. reported that VEGF expression as determined by in situ hybridization was an independent
prognostic factor for disease recurrence by multivariate analysis in 55 patients with muscle-invasive
bladder cancer treated with neoadjuvant MVAC
chemotherapy and radical cystectomy [85].
a) Matrix Metalloproteinase (MMP) and Tissue
Inhibitors of Matrix Metalloproteinase (TIMP)
A preliminary study evaluating the expression of
MMP-2, TIMP-2, and membrane-type matrix metalloproteinase-1 (MT1-MMP) by RT-PCR analysis in
41 bladder cancer patients indicated that high levels
of MMP-2, TIMP-2, and MT-1-MMP expression
were strongly associated with decreased survival
[382]. In a study of 97 urothelial cancer patients, the
serum MMP-2/TIMP-2 ratio, as determined by
enzyme immunoassay, was a significant and independent indicator of recurrence in advanced urothelial cancer patients in univariate and multivariate
analyses [383]. It remains unknown whether evaluation of the balance between the activity of MMPs
and that of their inhibitors (i.e., TIMP) in serum or
tissues can provide distinct information regarding
progression in patients with bladder cancer.
b) Thrombospondin-1 (TSP-1)
TSP-1 is an extracellular matrix glycoprotein that is
a potent inhibitor of angiogenesis. An IHC study
evaluating thrombospondin-1 expression in 163 cystectomy specimens showed that decreased TSP-1
expression was an independent predictor of disease
recurrence and overall survival after stratifying for
tumor stage, lymph node status, and histologic grade
[378]. Interestingly, TSP-1 expression was significantly associated with p53 expression status and
microvessel density counts [378].
b) E-cadherin
Decreased E-cadherin expression is generally correlated with increased muscle invasion and distant
metastasis as well as with higher tumor grade and
stage in patients with bladder cancer [384,385]. Ecadherin expression has been associated with overall
survival and recurrence-free survival [384,386-388]
In a cohort of 77 patients who underwent radical cystectomy, E-cadherin expression by IHC was significantly associated with disease progression and cancer-specific survival, and E-cadherin and stage were
independent predictors of disease progression [389].
c) COX-2
One IHC study of 108 patients treated with radical
cystectomy reported that COX-2 expression was
found in 31% of the cases and was correlated with
120
c) CD44
ly studied and may be promising molecular markers in predicting recurrence as well as progression of bladder cancer. However, even for p53 and
Ki-67, the data is still heterogeneous, because of
the lack of definitive criteria for test positivity, a
clearly defined patient population, required clinical and pathological standard tests for the staging
and grading of each tumor, and clearly defined
endpoints and statistical methods.
CD44 is a widely expressed cell surface adhesion
molecule involved in cell–cell and cell–matrix interactions. The variant exons (CD44v) are expressed
differentially according to cell and tissue type.
Recent data suggest that the ratio of the mRNA level
of the splice variant form of CD44 (=CD44v6-10) to
that of standard CD44 was closely associated with
the presence of tumor or with tumor progression
[390,391], indicating that the CD44 mRNA variant
may be a potential marker for bladder cancer screening.
As for the methodology, recent advances in molecular biology have provided various promising
techniques for exploiting and developing new
markers, including DNA and tissue microarray
technologies. However, these techniques still
require specialized personnel and equipment and
are time-consuming. From this point of view, IHC
is rather simple and is the most widely used
method for prognostic markers. However, as stated above, the results of different authors have to
be interpreted carefully since IHC is a multistep
procedure, with variations of antibodies and
condition of tissue sections, antibody concentrations, and incubation periods occurring among different institutions. Furthermore, standardized criteria for “positivity” should be established for each
marker. Therefore, multicenter studies for standardization of IHC detection methods and judgment
are ulti mately necessary for their successful and
consistent application. For example, in the case of
p53, a multicenter study of the Bladder Cancer
Marker Network indicated that, although there
was a high degree of agreement for p53-negative
samples or strongly p53-positive samples, a high
level of variability between laboratories and observers existed in the gray zone of low p53 positivity,
between 1% and 20% [1].
d) Urokinase-type Plasminogen Activator (u-PA)
Hasui et al. evaluated u-PA content in tumor tissue in
52 patients undergoing TUR, and the multivariate
analysis indicated that elevated u-PA content was the
most important risk factor for invasion and metastasis, compared with tumor stage, grade, multiplicity,
and size [392]. In a study including 51 patients who
underwent radical cystectomy, preoperative plasma
uPA level, but not urinary uPA level, was independently associated with metastases to regional lymph
nodes, lymphovascular invasion, disease progression, and disease-specific survival [393].
e) Multidrug Resistance (MDR)-related Proteins
(as a response marker)
Several multidrug resistance (MDR)-related proteins, such as P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), breast cancer resistance protein (BCRP), and lung cancer resistance-related protein/major vault protein (LRP/MVP), have been
identified. The relationship between chemo-resistance and the expression level of these proteins has
been investigated in many studies [394-398]. However, no large study to date has provided conclusive
data on their evaluation as chemosensitivity markers
in clinical settings.
Although some molecular markers (e.g., p53, Ki67) may be promising in predicting recurrence as
well as progression of bladder cancer, the results
of multi-center studies with a standardized methodology and cohort of patients are required to apply
these molecular markers to routine clinical decision-making.
Summary
Although significant correlations between various
laboratory markers and tumor progression have
been demonstrated, these tests have not been
adopted into standard practice yet and should not
significantly influence treatment decisions for
individual patients.
X. OVERALL SUMMARY
The usefulness of the currently available molecular markers as independent prognostic markers
still has to be determined in large prospective
comparative studies.
Heterogeneity of bladder tumors to invade and
metastasize and their frequent recurrence pose a
challenge for the physicians who treat bladder cancer
patients and for the researchers who work on bladder
Among the markers described in this section, p53
and Ki-67 labeling seem to be the most extensive
121
HAase, BLCA-4, cytokeratins (18, 19 and 20),
DD23, Immunocyt, survivin, Quanticyt, microsatellite analysis, telomerase (TRAP assay and hTERT
RT-PCR), and UroVysion have been tested for their
clinical usefulness. Some of these markers have also
been compared with each other and/or with cytology.
Case-control and cohort studies show that most of
these markers have significantly higher sensitivity
than cytology, and some also have the ability to
detect bladder tumor recurrence before it becomes
clinically visible. However, cytology is the superior
marker in terms of specificity, although some markers in limited numbers of studies have specificity
equivalent to that of cytology. As we learn more
about these markers through clinical trials and have
a better understanding of the conditions that cause
false positive or false negative results, it should be
possible to select a single marker or a combination of
markers that can accurately detect bladder cancer.
cancer diagnosis, recurrence, and treatment-related
areas. For the majority of new bladder cancer cases,
investigation begins when patients are symptomatic
(for example, with hematuria or irritative voiding).
This mode of detection is often inadequate for nearly 15% to 30% of these new cases that have highgrade bladder cancer, since the tumor is already in
the invasive stage at the time of diagnosis. Patients
with bladder cancer usually are followed on a 3- to
6-month surveillance schedule, since bladder tumors
frequently recur. The current mode of detecting bladder cancer involves cystoscopy, which is an invasive
and relatively expensive procedure. Voided urine
cytology, the standard noninvasive marker, is highly
tumor specific and has good sensitivity to detect high
grade tumors. However, its sensitivity to detect low
grade tumors is low, its accuracy depends upon a
pathologist’s expertise, and it is not readily available
in all countries.
Noninvasive tests that detect tumor-associated
molecules (such as enzymes, sugar polymers, and
tumor cell-associated proteins), altered gene expression, or chromosomal alterations would be useful for
detecting bladder cancer, evaluating its grade, monitoring recurrence, and predicting prognosis.
Several proliferation and metastasis-associated
molecules such as p53, Ki67, Rb, EGF-receptors, Ecadherin, cyclins, p21/WAF1, Kip1, and apoptosisrelated molecules have shown potential in providing
prognostic information related to metastasis, recurrence, and overall survival and cancer-specific survival. However, the results of many studies are contradictory, and there is no accurate marker as yet. The
ability to predict prognosis will improve as our
understanding of the biology of bladder cancer and
of the basis of molecular heterogeneity among bladder tumors of the same histologic grade and stage
improves. Development of reliable and accurate
detecting methods will also improve the acceptability of prognostic markers among physicians.
Due to the low prevalence of bladder cancer, screening of the general population for bladder cancer
using noninvasive tests is not cost-effective. However, noninvasive tests may be effective in screening
and in early detection of bladder cancer among highrisk individuals. The most practical use of noninvasive tests would be for monitoring bladder cancer
recurrence and reducing the number of surveillance
cystoscopies performed each year.
For a noninvasive test to become clinically useful, it
should be easy to perform, have low-intra-assay and
interassay variability, have minimum requirements
for sample handling and preparation, and be reliable.
A noninvasive test should have high sensitivity and
specificity in order to minimize the false negative
and false positive cases, respectively. Due to highly
sensitive detection methods, many noninvasive tests
might detect a bladder tumor before it becomes clinically visible. The risk ratio and the odds ratio calculated for the false positive results on a noninvasive
test should help physicians in making treatment decisions based on positive test results in the absence of
clinical evidence of bladder cancer.
The field of noninvasive bladder tumor markers and
prognostic indicators is rapidly expanding. Although
none of the noninvasive markers or tests can replace
cystoscopy, at the present time, certainly many markers together with cystoscopy can improve the current
practice of managing bladder cancer patients. Several bladder cancer markers have higher sensitivity,
specificity, positive predictive value and negative
predictive value for detecting bladder cancer than
PSA has for detecting prostate cancer. Ultimately, the
confidence of both physicians and patients to accept
tumor markers in the management of bladder cancer
patients will decide whether any of the current, or yet
to be discovered, markers will reach the status as a
“PSA for bladder cancer ” [399].
Several tumor markers and tests such as hemoglobin
dipstick, BTA-Stat, BTA-TRAK, NMP-22, HA-
122
RECOMMENDATION
I. STANDARD CARE FOR BLADDER CANCER DETECTION AND SURVEILLANCE
IV. GOOD CLINICAL PRACTICE IN
MARKER DEVELOPMENT
1. Cystoscopy and pathologic examination of biopsy
specimens is the standard of care for the detection
of bladder cancer.
1. Efforts should be supported to standardize tumor
marker development.
2. General guidelines and protocols for broadly
accepted principles of the design of marker studies should be developed and made available for
discussion to reach consensus.
2. Periodic cystoscopies are the standard of care for
surveillance. Surveillance schedules vary according to the risk factors of the disease.
3. Different phases of tumor marker development for
conducting, reporting, and reviewing translational marker studies should be followed.
II. BLADDER TUMOR MARKERS : WHY DO
WE NEED THEM?
4. Indicating the developmental stage of a given marker may help to identify its usefulness for either
further evaluation or clinical application.
1. Screening of high-risk, but not the general population, using bladder tumor markers can offer early
detection advantage and save medical costs.
2. More studies are needed to identify accurate markers for bladder cancer screening.
V. URINE CYTOLOGY: THE STANDARD
NONINVASIVE BLADDER TUMOR
MARKER
3. Bladder tumor markers with high negative predictive values can be used in monitoring recurrence,
not to replace cystoscopy, but to prolong the
interval between examinations.
1. Urine cytology is the standard noninvasive
method for detecting bladder cancer.
4. Prospective trials are needed to determine the cost
savings, change in quality of life, and safety of
this strategy.
2. The diagnostic yield of urine cytology is increased
if at least 3 samples are analyzed.
III. IDEAL TUMOR MARKER
4. Cytology has high sensitivity and negative predictive value to detect high grade bladder tumors.
3. Bladder washings may be better than voided urine
for the evaluation of exfoliated urothelial cells.
1. For a biomarker to be clinically useful, it should
have technical simplicity, reliability, and high
accuracy (i.e., high sensitivity and specificity).
5. Cytology has low sensitivity and negative predictive value to detect low grade bladder neoplasms.
6. Cytology has superior specificity than most of the
currently available bladder tumor markers.
2. A clinically useful marker should have high positive predictive value to avoid unnecessary workup due to false positive results.
3. A biomarker should have a high negative predictive value in order to avoid the risk of bladder cancer progression due to missed tumor detection.
VI. BLADDER TUMOR MARKERS FOR
DIAGNOSIS AND MONITORING
RECURRENCE
4. The physician’s dilemma related to the possible
early detection of bladder cancer by biomarkers
could be decreased by examining the risk of
developing bladder cancer in a specified time
when a biomarker is positive.
1. SOLUBLE URINE MARKERS
a) Hematuria Detection
1. Hematuria detection is a useful first-line marker to
detect urologic diseases including urologic malignancies.
2. In general, hematuria detection has high sensitivity but low specificity to detect bladder cancer.
123
4. Since cytokeratin markers have high false positive
rates when several urologic conditions other than
bladder cancer are present, the clinical utility of
these markers may be limited.
However, the sensitivity of hematuria detection
may suffer due to the intermittent nature of hematuria.
3. Hematuria testing by hemoglobin dipstick is
reliable and superior to microscopic examination
of RBCs.
g) HA-HAase test
1. The HA-HAase test has high sensitivity and specificity to detect both primary and recurrent bladder tumors and to evaluate their grade.
b) BTA-Stat and BTA-TRAK
1. The sensitivity of BTA-Stat and BTA-TRAK tests
is dependent on tumor grade, stage, and size.
2. This test may provide an early detection advantage.
2. The specificity of BTA-Stat and BTA-TRAK is
high among healthy individuals but is low among
patients with various benign genitourinary conditions.
3. The accuracy of this potentially useful test needs
to be evaluated in larger multicenter trials.
2. CELL-BASED MARKERS
c) NMP-22
a) Microsatellite Analysis
1. The NMP-22 test may provide adjunctive information in monitoring bladder cancer recurrence.
• The clinical applicability of these markers is limited at this time because of the lack of consensus
on the types and number of markers to be used, as
well as a need for expensive equipment and trained personnel for conducting the analysis.
2. The sensitivity of NMP-22 is not high enough to
eliminate current cystoscopy for bladder cancer
detection and monitoring recurrence.
3. Due to relatively low specificity, its routine use for
the detection of bladder cancer is not recommended.
b) Telomerase
1. Telomerase detection by TRAP assay or hTERT
RT-PCR has higher sensitivity than conventional
cytology regardless of tumor grade and stage.
d) BLCA-4 and BLCA-1
1. BLCA-4 is a potentially useful marker for the
detection of bladder cancer, as it detects bladder
cancer with both high sensitivity and specificity.
2. TRAP assay or hTERT RT-PCR are not recommended in routine clinical settings because of the
lack of standardization of sample processing,
complicated laboratory procedures, and the lack
of standardized methods to eliminate factors
which cause false positive and false negative
results.
2. Large multicenter clinical trials will validate the
efficacy of these potentially useful markers.
e) Survivin
c) u-Cyt
• Due to the limited number of studies conducted on
this marker, which involved relatively small
numbers of patients with bladder cancer and relevant controls, recommendations cannot be made
at this time.
1. The uCyt assay is superior to conventional urine
cytology and appears to be a promising diagnostic marker for bladder cancer.
2. The uCyt assay is an observer-dependent technique requiring a broad personal experience and
constant quality control.
f) Cytokeratins
1. The UBC-Rapid and UBC-IRMA tests may have
limited clinical applicability due to lower sensitivity to detect bladder cancer when compared to
other bladder tumor markers.
3. Prospective trials designed to evaluate the role of
this test in the management of bladder cancer
appear worthwhile.
2. Cytokeratin-20 (RT-PCR or immunohistochemistry) may be a useful marker to detect bladder cancer.
d) DD23
1. This immunocytology-based test has high sensitivity but low specificity to detect bladder cancer.
3. Limited data are available on CYFRA 21-1 and
thus recommendations cannot be made on this
marker.
2. The combination of DD23 with cytology could be
used to decrease the frequency of cystoscopy.
124
cohort of patients are required to apply these molecular markers to routine clinical decision-making.
3. A prospective trial to evaluate the usefulness of a
combination of DD23 and cytology should be
conducted.
e) Quanticyt Nuclear Karyometry
ACKNOWLEDGMENTS: We acknowledge the
editorial assistance of Dr. Adrienne Carmack. This
work was supported for the following grants:
NCI/NIH R01 CA-72821-06A2 [Vinata B. Lokeswhar, PhD].
1. This is a useful marker to stratify patients into
low-, intermediate-, or high-risk for bladder cancer.
2. Due to the requirement for sophisticated instrumentation, bladder wash specimens, and technical expertise, the general applicability of this
marker is limited.
f) UroVysion Test
1. The UroVysion test appears to be a promising test
for detecting bladder cancer and monitoring its
recurrence. However, the test has low sensitivity
to detect low grade bladder tumors.
2. Development of a consensus for the criteria used
for the evaluation of abnormal cells is needed to
improve the test’s clinical applicability.
3. UroVysion is an observer-dependent technique
requiring trained personnel, sophisticated instrumentation, and constant quality control.
4. A positive UroVysion may be indicative of both
the neoplastic transformation (i.e., presence of
bladder cancer) and an unstable urothelium primed for malignant transformation.
VII. COMPARATIVE ANALYSIS OF
BLADDER TUMOR MARKERS
1. Several noninvasive tests are more sensitive than
cytology.
2. Noninvasive tests with a high sensitivity and reasonable specificity can be used in a surveillance
setting to reduce the number of cystoscopies performed each year for monitoring bladder tumor
recurrence.
3. Due to the limited amount of data, no tumor marker can be recommended for use in bladder cancer screening at this time.
VIII. PROGNOSTIC MARKERS FOR
BLADDER CANCER
Although some molecular markers (e.g., p53, Ki-67)
may be promising in predicting recurrence as well as
progression of bladder cancer, the results of multicenter studies with a standardized methodology and
125
Bethesda, Maryland, http:// seer. cancer. gov/csr/ 1975_2001/
,2004.
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137
138
Committee 3
Low Grade, Ta (Noninvasive)
Urothelial Carcinoma of the Bladder
Chairs
W. OOSTERLINCK (BELGIUM)
E. SOLSONA (SPAIN)
Members
H. AKAZA (JAPAN)
C. BUSCH (SWEDEN)
P. J. GOEBELL (GERMANY)
P.-U. MALMSTRÖM (SWEDEN)
H. ÖZEN (TURKEY)
P. SVED (USA)
139
CONTENTS
VII. PROGNOSTIC FACTORS AND
FOLLOW-UP
I. INTRODUCTION
1. DEFINITION
2. PRIMARY DIAGNOSIS
1. PROGNOSTIC FACTORS
2. FOLLOW-UP
II. ACCURACY OF CYSTOSCOPY IN
DEFINING PAPILLARY TUMORS
VIII. OFFICE FULGURATION OF
RECURRENT LOW GRADE Ta
TUMORS
III. UPPER URINARY TRACT
EXPLORATION IN LOW GRADE Ta
UROTHELIAL CARCINOMA OF
THE BLADDER
1. FEASIBILITY
2. EFFICACY
IX. URINE CYTOLOGY AND URINEBASED MARKERS IN LOW GRADE
Ta UROTHELIAL CARCINOMA OF
THE BLADDER
1. UPPER URINARY TRACT EXPLORATION AT
INITIAL DIAGNOSIS
2. UPPER URINARY TRACT EXPLORATION
DURING FOLLOW-UP
3. PROGNOSIS
4. SYMPTOMATIC PATIENTS
1. INITIAL TUMOR GRADE
2. PRESENCE OF ASSOCIATED CARCINOMA IN
SITU
3. URINARY MARKERS IN FOLLOW-UP
IV. PRIMARY TREATMENT OF LOW
GRADE Ta UROTHELIAL
CARCINOMA OF THE BLADDER
X. LIFESTYLE, DIET, AND FOOD
SUPPLEMENTS
1. SMOKING
2. FLUID INTAKE
3. FRUITS AND VEGETABLES
4. VITAMIN A
5. VITAMIN C
6. VITAMIN E
7. VITAMIN B
8. VITAMIN COMBINATIONS
9. LACTOBACILLUS CASEI AS A PROPHYLACTIC AGENT FOR RECURRENCE OF
SUPERFICIAL BLADDER TUMORS
1. RANDOM BIOPSIES
2. SECOND RESECTION
V. ONE EARLY PERIOPERATIVE
INSTILLATION OF
CHEMOTHERAPY
1. HISTORY
2. META-ANALYSIS OF EFFICACY
3. WORKING MECHANISM
4. DURATION OF THE EFFECT
5. TIMING OF THE INSTILLATION
6. INTRAVESICAL DRUGS
7. COST-EFFECTIVENESS
8. TOXICITY
9. PRECAUTIONS
RECOMMENDATIONS
ALGORITHM
VI. FURTHER INTRAVESICAL
CHEMOTHERAPY
REFERENCES
1. DOSE AND SCHEDULE
2. THE ROLE OF BCG
140
Low Grade, Ta (Noninvasive)
Urothelial Carcinoma of the Bladder
W. OOSTERLINCK, E. SOLSONA
H. AKAZA, C. BUSCH, P. J. GOEBELL, P.-U. MALMSTRÖM, H. ÖZEN, P. SVED
devoted to a discussion of urothelial (transitional
cell) carcinoma.
I. INTRODUCTION
Further subclassification is based on two pillars :
The low grade urothelial neoplasms have a clearly
different and better outcome than higher grade
tumors. While they rarely evolve to a fatal cancer,
recurrence of these neoplasms remains a major problem, requiring adjuvant therapies after transurethral
resection (TUR) and long-term follow-up. We have
moved from using the word cancer when describing
these tumors, avoiding the psychologic impact of
this word on patients. The term urothelial neoplasms
better describes the matter.
1. The TNM classification, which provides a system
for staging. T refers to the primary tumor and the
extent of tumor involvement at the primary site, N
refers to the lymph node status, and M to the presence or absence of distant metastases. Presently,
the TNM classification from 2002 is widely
accepted [2].
2. The histological grade, which refers to the appearance of the cancer cells under the microscope. In
1998 a new classification of noninvasive urothelial tumors was proposed at the WHO and International Society of Urological Pathology (ISUP)
consensus meeting. The new classification system
for grading urothelial neoplasms was published by
the World Health Organization (WHO) in 2004
(Table 1) [3]. The objective with this new version
was to avoid the overdiagnosis of cancer and to
create better criteria for the different grades. Prior
to this classification system, numerous diverse
grading schemes for bladder cancer existed. Thus,
the same lesion seen by different pathologists
would result in very different diagnoses solely
based on differences in definitions. Unfortunately,
the new system has not been as universally
accepted as the recent TNM classification.
The term noninvasive is used here to refer to Ta disease. The term superficial is vague, and may include
both Ta and T1 tumors. It is used only when referring
to studies of both types of tumors.
Noninvasive tumors are the most common presentation of urinary bladder cancer and constitute almost
half of all newly-diagnosed patients. In a populationbased study from western Sweden, 53% of patients
with a first diagnosis of bladder carcinoma had papillary stage Ta disease. Seventy percent of these were
low grade carcinomas (Level 2, [1]). The incidence
is low below the age of 50 but thereafter steadily
grows in frequency.
1. DEFINITION
The diagnosis of bladder cancer ultimately depends
on cystoscopic examination of the bladder and
pathologic evaluation of the resected or biopsied
lesion. Macroscopically, a lesion is either papillary,
solid, flat, or a mixture of these configurations.
In the new WHO 2004 classification, grade 1 tumors
were reclassified either as papillary urothelial neoplasms of low malignant potential (PUNLMPs) or
true low grade tumors. The grade 2 tumors are
reclassified either to low grade or high grade tumors
according to specific cytologic and architectural criteria. The terminology used in the new grading system parallels that used in urinary cytology (see
Chapter 1: Epidemiology, Staging and Grading, and
Histopathologically, more than 90% of bladder cancer cases are urothelial (transitional cell) carcinoma,
approximately 5% are squamous cell carcinoma, and
less than 2% are adenocarcinoma. This chapter is
141
Table 1. Nomenclature of Grade Classes (According to
WHO 2004) [3]
Papilloma
Papillary urothelial neoplasm of low malignant potential
(PUNLMP)
Low grade carcinoma, grade I
High grade carcinoma, grade II
High grade carcinoma, grade III
Diagnosis). A web site illustrating examples of various grades was developed: www. pathology. jhu.edu/
bladder. The cells in PUNLMP look very much like
normal bladder cells and are slowly growing and
unlikely to progress. Nevertheless, PUNLMPs still
have a high tendency, although lower than for grade
1 tumors, to recur (Level 3). The differences in recurrence and progression rates justify the distinct classification of PUNLMPs and grade 1 tumors (Level 3,
[1,4]).
Figure 1. Low Grade Papillary Urothelial Carcinoma
Herr correlated the cystoscopic appearance of recurrent superficial papillary bladder tumors with histology after TUR in 150 consecutive patients (Level 3,
[5]). Papillary lesions were classified as TaG1, TaG3,
or T1G3 based on their cystoscopic appearance.
Tumors classified as TaG1 were less than 0.5 cm and
had individually discrete papillary fronds of mucosa
surrounding a clearly visible fibrovascular core.
Tumors with fused or less discrete papillary fronds
that occurred in clusters or were greater than 0.5 cm
in diameter were usually graded TaG3. Lesions that
appeared papillonodular or solid were classified as
T1. These latter tumors were all larger than 0.5 cm.
Voided urine cytology was also obtained in each
case. Of 84 tumors regarded as TaG1 at cystoscopy,
93% (78/84) proved to be low grade papillary tumors
histologically. Seventy-two patients had a cystoscopic TaG1 tumor and negative urine cytology. Of these,
98% (71/72) were TaG1 histologically. Of the 84
papillary tumors that appeared to be low grade, 6 of
84 (7%) were high grade and 2 of 84 (2%) were confirmed on biopsy to be invasive. Only 3 of 66 (4.5%)
tumors considered to be high grade at cystoscopy
proved to be low grade histologically.
2. PRIMARY DIAGNOSIS
The vast majority of the papillary tumors are detected by the presence of hematuria. Sometimes it may
be detected on evaluation for a recurrent urinary tract
infection or incidentally by ultrasound, which is
often performed as an exploration for hematuria.
Bladder irritation in the absence of infection may be
a symptom of bladder carcinoma but not of a low
grade Ta lesion.
Cystoscopy is the method by which most of the papillary tumors are detected.
Urinary cytology will be negative in the majority of
low grade tumors but is useful at first diagnosis as it
predicts the presence of high grade tumors. The role
of urinary markers is not yet clearly defined (see
Section IX).
In a similar study from the same institution, Herr
evaluated the correlation between cystoscopic
appearance and histopathology in 125 patients with
144 recurrent papillary tumors (Level 3, [6]). Consistent with their previous findings, 90 of 97 tumors
(93%) considered TaG1 at cystoscopy were confirmed on biopsy to be low grade papillary lesions.
Of the 86 TaG1 tumors associated with negative
urine cytology, 85 (99%) proved to be low grade
papillary tumors histologically. Only 1 of 97 (1%)
tumors deemed TaG1 proved to be invasive by biopsy. Of lesions believed to be high grade or invasive,
only 6 of 47 (13%) were overgraded by cystoscopic
II. ACCURACY OF CYSTOSCOPY IN
DEFINING PAPILLARY TUMORS
Outpatient fulguration has become increasingly popular in the management of recurrent, low grade papillary tumors of the bladder. In order to justify this as
definitive treatment of such lesions, the urologist
must be able to accurately distinguish the cystoscopic features of low grade, noninvasive from high
grade, potentially invasive tumors (Figure 1).
142
appearance. The authors concluded that since the
overwhelming majority of tumors which appear to be
low grade on cystoscopy prove to be low grade on
biopsy, these lesions may be safely managed with
fulguration alone, especially in the setting of negative urine cytology.
negative urine cytology, low grade papillary neoplasms may be identified accurately in over 90%
of cases (Level 3, [6,7]). Because of the potential
for undergrading, lesions with the following characteristics should be evaluated further : lesions
larger than 0.5 cm in diameter, multiple lesions
(>5), those which are papillonodular, and those
associated with positive urine cytology.
Oosterlinck et al., in a multi-institutional study,
reported that 5.6% of 501 tumors believed to be noninfiltrating at cystoscopy were understaged compared to histopathology (Level 2, [7]). Tumors
appearing superficial that were less than 3 cm in
diameter were correctly staged in 96% of the cases.
No data were available regarding the accuracy of
cystoscopy in predicting tumor grade. In this
EORTC study, the investigators were asked to
include patients before histology was available. The
number of patients not included because of doubtful
interpretation was not reported.
III. UPPER URINARY TRACT
EXPLORATION IN LOW GRADE Ta
BLADDER TUMORS
1. UPPER URINARY TRACT EXPLORATION AT
INITIAL DIAGNOSIS
Other authors reported the potential inaccuracies of
cystoscopic evaluation of bladder tumors. Cina et al.
reported that 7 of 13 (54%) papillary lesions confirmed to be high grade by biopsy were believed to
be low grade based on their cystoscopic appearance
(Level 3, [8]). Of 37 lesions believed to be low grade
on cystoscopy, 7 of 37 (19%) proved to be high grade
at biopsy. Of 7 invasive lesions, 3 were believed to
be noninvasive at cystoscopy. Of 9 lesions considered high grade at cystoscopy, 33% were low grade
by histologic examination. One remarkable finding
from this study was the excellent accuracy (100%) in
differentiating neoplastic from non-neoplastic
lesions (such as inflammation or denuded urothelium) by solely using cystoscopic evaluation. The
authors concluded that grade and stage of papillary
neoplasms could not be accurately predicted by cystoscopic appearance alone.
The need for upper urinary tract imaging when the
initial diagnosis of bladder tumors is made is rather
questionable [9]. An intravenous urography at initial
diagnosis is performed not only for the detection of
upper urinary tract tumors, but also for the diagnosis
of other asymptomatic diseases such us obstruction
or lithiasis.
a) Incidence
In patients with bladder cancer in general, the incidence of upper urinary tract tumors at the time of
diagnosis is very low, ranging from 0.3% to 2.3%
(Level 3, [9,10,12,13]). After analyzing different
bladder tumor characteristics, a relationship has been
observed between grade and stage of bladder tumor
and the incidence of synchronous upper urinary tract
tumors: 0 of 78 (0%) for grade 1, 4 of 361 (1.1%) for
grade 2, and 5 of 360 (1.3%) for G3, as well as 1.2%
for stage Ta to T1, 0% for Ta, and 7% for T1 [10]. In
patients with TaG1 or G2 tumors, the incidence of
synchronous upper urinary tract tumors is extremely
low. Initial intravenous urography also detected 18%
of other pathologies, 5.8% unsuspected, but only
1.4% required additional treatment, which did not
affect the planned TUR [10]. In other series, only
0.3% of patients needed additional therapy based on
intravenous urography findings. Most of the obstructive problems were also documented by ultrasound,
routinely carried out as part of the work-up of these
patients [9].
The contradiction between the two first and the last
paper can be explained by a different selection of
cases. In Herr’s study, only recurrences of Ta or T1
tumors with previous known histology were examined. Oosterlinck’s study mainly investigated small,
new solitary tumors, while in Cina’s study results of
TUR specimens without any preselection were studied.
Summary
In summary, these studies show that conflicting
data exists regarding the ability of cystoscopic
appearance to accurately predict the stage and
grade of papillary tumors of the bladder. However, in experienced eyes, and in combination with
b) Reliability of Intravenous Urography
In the diagnosis of upper urinary tract tumors, the
reliability of intravenous urography is unsatisfactory,
143
ranging from 30% to 70% (Level 3, [10,14,15]). To
define the final diagnosis, additional procedures are
necessary in all of the remaining patients.
and even longer for patients at low risk (Level 3, [13,
15, 16, 25]). This long interval means that prolonged
follow-up for the diagnosis of metachronous upper
urinary tract recurrence in patients with TaG1 or G2
tumors would be necessary, requiring a large amount
of intravenous urographies. The toxicity of this diagnostic procedure is present, with 0% to 4.6% rates of
nephrotoxicity and a 1.6% incidence of anaphylactic
reactions. However, with nonionic contrast medium,
the toxicity decreases (Level 3, [10]).
2. UPPER URINARY TRACT EXPLORATION
DURING FOLLOW-UP
Whether or not to follow patients diagnosed with
bladder cancer with intravenous urography is another controversial issue [14-17]. Holmäng et al.
observed an incidence of upper tract tumors of 2.9%
in patients with bladder cancer: 0.4% for G1, 1.3%
for G2, and 0.8% for TaG1 or G2 tumors [11]. Recommendations on how to follow these patients are
inconsistent; some authors recommend not following
these patients with intravenous urography, while others recommend an investigation of the upper urinary
tract every year, every 2 years, every 3 years, or
every 5 years (Level 3, [11,14,15,17,18]).
c) Upper Urinary Tract Cytology
Including routine upper urinary tract cytology in the
follow-up of patients with TaG1 or G2 bladder
tumors is not justified given the low incidence of
upper tract recurrence and the lack of cytology specificity for localizing urothelial carcinoma in patients
with bladder cancer (Level 3, [28,29]).
a) Incidence
3. PROGNOSIS
As a whole, the incidence of metachronous upper
urinary tract tumor after bladder tumor ranges from
0.7% to 5.9% (Level 3, [14,15,19-21]). However, this
incidence increases to 13.5% to 19% in high-risk
patients and to 21.2% to 29% in patients with associated bladder carcinoma in situ (CIS) (Level 3, [16,
22-25]). More specifically, during follow-up the incidence of upper urinary tract tumor for patients with
no bladder CIS drops to between 2.3% and 3.1%,
0.9% for low-risk patients, and 2.5% for patients
with TaG1 or G2 tumors (Level 3, [11, 16, 24, 26]).
Whether upper tract tumors detected in asymptomatic patients have a better prognosis than those detected after symptoms develop is unknown. The presence of upper urinary tract tumors initially or after
resection of bladder cancer has a negative impact on
survival in several series, but this event is usually
assessed in high-risk superficial bladder tumors
(Level 3) [22, 26, 30]. However, the prognosis of
patients with upper tract tumors diagnosed after
superficial bladder cancer is better than patients with
primary upper urinary tract tumors, based on information from the SEER database (Level 3, [21]). As a
whole, there is no clinical evidence that an early
diagnosis improves the prognosis of patients with
upper urinary tract disease diagnosed after bladder
tumors (Level 3, [22, 23]). Also, a relationship
between the grade and stage of bladder and grade
and stage of upper urinary tract tumors has been
reported, with a potential better prognosis for
patients with TaG1 or G2 bladder tumors (Level 3,
[15]). In summary, although there is no clinical evidence, the prognosis of patients with bladder TaG1
or G2 tumors does not seem to be threatened by a
delay in diagnosis of upper tract tumors until the
presence of positive urinary cytology or development of symptoms.
A relationship between vesicoureteral reflux after
TUR of a bladder tumor and upper tract recurrence
has been reported: the incidence increased from
0.4% to 0.9% in those patients without reflux to
6.4% to 19.7% in patients with reflux (Level 3, [15,
19,20]). However, the vast majority of patients with
reflux and recurrence also had associated high risk
factors for upper tract recurrences (bladder CIS, G3
or recurrent tumors). In multivariate analyses, multifocality and the presence of bladder CIS are independent factors for upper urinary tract recurrence in
patients with bladder tumors (Level 3, [16,27]), but
reflux has not been evaluated. In the absence of multivariate analysis including vesicoureteral reflux, its
real responsibility in the development of upper urinary tract tumors is not well-established.
4. SYMPTOMATIC PATIENTS
b) Interval From Diagnosis of Bladder Tumor and
Upper Urinary Tract Recurrence
The assessment of the upper urinary tract in symptomatic patients or those with positive urinary cytology but no bladder tumors is completely justified as
part of the diagnostic work-up (Level 3, [31]).
The reported intervals are extremely wide, with the
mean interval ranging from 5.4 months to 6.2 years
144
Summary
visible recurrences within 4 weeks of primary resection, the detection of residual tumors with random
bladder biopsies is very low [33]. The recurrence rate
at 3 months also remains low in this best prognosis
group of superficial bladder cancer. As such, it seems
unrealistic to expect that the second resection will
reveal substantial findings that will change treatment
and outcome for the patient in this particular group
of superficial bladder cancer. Therefore, a second
resection is not indicated if no visible recurrences are
present (Level 2).
In patients with TaG1 or G2 bladder tumors, the
low incidence of upper urinary tract tumors, the
need for an extremely prolonged follow-up, the
potential minimal prognostic impact of a delay in
diagnosis, and the high cost of repeated intravenous urography do not support routine upper urinary tract assessment during follow-up. This was
also the conclusion of the guidelines panel of the
European Association of Urology (EAU) on upper
urinary tract tumors (Level 3, [32]).
V. ONE EARLY PERIOPERATIVE
INSTILLATION OF
CHEMOTHERAPY
IV. PRIMARY TREATMENT OF LOW
GRADE Ta UROTHELIAL
CARCINOMA OF THE BLADDER
1. HISTORY
The TUR for low grade Ta bladder tumors of course
is not different from the TUR for any other superficial bladder cancer (See Chapter 1).
2. SECOND RESECTION
The instillation of a chemotherapeutic drug immediately after TUR is an old idea which was initially
tested in the 1970s [40, 41]. It was based on the fact
that chemotherapy would be able to destroy floating
tumor cells and prevent implantation at any traumatized surface of the bladder. This theory was strongly supported by animal experiments [59]. At that
time, mainly thiotepa was used. Later, doxorubicin
(Adriamycin) and epirubicin (Epodyl) were also
evaluated. These first clinical trials suggested a
reduction in the rate of tumor recurrence when a
perioperative instillation was given [42,43]. After
these preliminary results, the need for properly conducted, large scale, randomized controlled studies
became evident. The first important study in this
regard came from the British Medical Research
Council (MRC). Four hundred seventeen patients
with newly diagnosed superficial bladder tumors
were treated with a complete TUR and then randomized to 1 of 3 groups [44]. Groups 1 and 2 received
an instillation of 30 mg of thiotepa at the time of
TUR; thereafter, patients in group 2 also received
instillations of thiotepa every 3 months for a year.
Group 3 was a control group in which no instillation
was given. Neither the first publication of the MRC
in 1985, nor the second publication of the results
with longer follow-up in 1994 showed any differences in the recurrence rates among the 3 groups
[44,45]. However, subsequent randomized studies
have shown impressive improvements of the recurrence-free rate (Level 2, [36,48-53]).
In clinical trials controlling for the number of early
Despite the scientific evidence provided, a single
1. RANDOM BIOPSIES
A low grade superficial bladder tumor is expected
when urinary cytology does not show malignant
cells, when no suspicious red zones suggest CIS, and
when the tumor has a nice papillary structure. In
these conditions, random biopsies are inappropriate
and do not provide any additional information relevant for the treatment and the prognosis of superficial bladder cancer (Level 2, [33-35]). The number of
abnormalities detected in these cases will be very
low (Level 1, [36]). Publications emphasizing the
need for random biopsies particularly report the
detection of CIS (Level 2, [37]). This disease will,
however, be detected by a positive cytology. Identifying an additional small but invisible Ta or T1
lesion does not alter treatment or prognosis in a substantial way.
Any traumatized bladder mucosa may become an
implantation site for floating tumor cells. Although
there is no clinical evidence for this phenomenon,
there are animal experimental data demonstrating
this [38,39]. Among possible explanations for the
high rate of early recurrences of superficial bladder
cancer is the theory of implantation of cells shed during TUR.
145
immediate postoperative instillation has not become
routine procedure. The EAU guidelines were the first
guidelines advocating for 1 single immediate instillation after TUR in all patients with superficial bladder tumors [53]. As 1 single instillation has been
mainly tested in low-risk tumors, there was still
doubt regarding the value of 1 immediate instillation
in patients with multiple tumors, who are at a higher
risk for recurrence. There was also no consensus if
all patients with a single, low risk tumor should
receive intravesical chemotherapy after the initial
TUR. This was mainly the reason to perform a metaanalysis of the published results of randomized clinical trials with 1 single immediate postoperative
instillation of chemotherapy in patients with stage Ta
or T1 bladder cancer.
could not be done in the meta-analysis due to the
absence of individual patient data, but the 2 other
studies in which they were performed suggest that
the treatment is beneficial across all categories of
patients [36, 52].
3. WORKING MECHANISM
The effect of 1 instillation may be explained either
by the chemoresection of tumor left behind after an
incomplete TUR or by destroying circulating tumor
cells that could implant at the site of resection.
Incomplete TUR may be an issue even in patients
with solitary tumors as seen by the large variation
between institutions in the recurrence rate at the first
follow-up cystoscopy after TUR [56]. Oosterlinck et
al. found that 10 patients out of 242 had residual
tumors 1 month after TUR, only 1 of which was in
the instillation arm [36]. Masters et al. found a 44%
complete response rate in a marker lesion 3 months
after 1 instillation of epirubicin [57]. Thus, 1 instillation can in fact eradicate tumor left behind after
TUR.
2. META-ANALYSIS OF EFFICACY
Sylvester et al. included 7 randomized trials with
recurrence information on 1476 patients in their
meta-analysis (Level 1, [54]). Based on a median follow-up of 3.4 years and a maximum of 14.5 years,
267 of 728 patients (36.7%) receiving 1 postoperative instillation of epirubicin, mitomycin C (MMC),
thiotepa, or pirarubicin experienced a recurrence as
compared to 362 of 748 patients (48.4%) with TUR
alone (odds ratio [OR] 0.61, P < 0.0001). This metaanalysis has shown that 1 immediate instillation of
chemotherapy after TUR decreases the relative risk
of recurrence by 39% in patients with Ta or T1 bladder cancer.
Supporting the hypothesis of implantation of circulating tumor cells, Whelan et al. found that postoperative irrigation with saline or glycine for 18 hours
significantly prolonged the time to first recurrence,
with a reduction of 17% in the relative risk of recurrence [38,58]. Several animal experiments also support the hypothesis of tumor implantation at traumatized areas in the bladder [39,59].
4. DURATION OF THE EFFECT
Although the majority of the patients included in
these randomized trials had a single tumor, it was
found that both patients with a single tumor (OR
0.61) and those with multiple tumors (OR 0.44) benefited from a single instillation. However, after 1
instillation, 65.2% of the patients with multiple
tumors had a recurrence compared to 35.8% of the
patients with a single tumor, showing that one instillation alone is suboptimal treatment in patients with
multiple tumors. In a trial excluded from the metaanalysis because some patients received additional
instillations before recurrence, Zincke et al. also
found that patients with multiple tumors benefited
from an immediate instillation of thiotepa or doxorubicin [55]. Defining risk groups according to
whether the tumor was single or multiple and the
result of the first follow-up cystoscopy, Tolley et al.
found that the benefit of MMC in both treatment
groups combined was similar in low-, medium-, and
high-risk cases [46, 47]. Other subgroup analyses
In those studies in the meta-analysis with the information available, Kaplan-Meier time-to-first-recurrence curves showed that the time point at which the
treatment benefit started varied somewhat: in 3 studies there was a reduction in the percent of patients
with residual tumors at 1 month or with recurrence
already at 3 months and in 1 study the benefit
appeared starting at 6 months [36,49,52]. However,
in another study the treatment effect appeared only
starting at 1 year [36]. As suggested by Solsona et al.,
the effect of 1 instillation appears to occur early,
mainly during the first 2 years, with a possible dilution of the treatment effect with longer follow-up
[49]. Investigating the percentage of patients who
experience recurrence rather than considering the
time to first recurrence may in fact underestimate the
size of the treatment effect. However, with long-term
follow-up it is clear that 1 immediate instillation prevents, rather than simply delays, recurrences.
146
5. TIMING OF THE INSTILLATION
have appeared on severe and prolonged complications due to extravasation of the drug after an early
intravesical instillation. Doherty at al. reported the
local effects of an immediate instillation of
chemotherapy (mainly epirubicin) in cystectomy
specimens [63]. It was associated with a more extensive necrosis of the bladder wall and fat necrosis of
extravesical tissue than the usual muscle necrosis
seen after TUR alone. An area of thin muscularis
propria may undergo necrosis resulting in secondary
perforation. None of the 12 patients described by
Doherty et al., however, reported local symptoms. In
contrast, the effect of extravasation after intravenously administered chemotherapeutic drugs is
well-documented. It induces long-lasting necrosis,
provoking pain with a low tendency of healing.
Recently, several cases of severe and long-lasting
complications due to extravasation of MMC have
been reported [64]. A distal ureteral stenosis has also
been described that was probably due to intravesical
MMC [65]. There is certainly an underreporting of
these complications as not every urologist who has
seen such a complication is eager to report such an
event. In any case, urologists should be aware of the
potential risk of extravasation of chemotherapeutic
drugs and its consequences.
In all studies, the instillation was given within 24
hours, generally either immediately after TUR or
within 6 hours after. Kaasinen et al. found a doubling
in the risk of recurrence if the first of 5 weekly MMC
instillations was not given on the same day as the
TUR in patients with frequent recurrences [60]. In 2
EORTC trials where patients received 9 instillations
of epirubicin or MMC over 6 months, starting treatment on the day of TUR was more effective than
starting 7 to 15 days later in patients who did not
receive further maintenance after 6 months (Level 2,
[61]). In another study where patients received 15
instillations of doxorubicin or MMC over 1 year,
fewer patients randomized to start treatment within 6
hours recurred as compared to patients randomized
to start treatment after 7 to 14 days, especially in the
MMC arm (Level 2, [62]). There is thus some evidence that the instillation should be given on the
same day as the TUR.
6. INTRAVESICAL DRUGS
With the possible exception of the 1 study with
thiotepa in which no difference was found, the metaanalysis suggests that no large differences exist with
regard to efficacy between the different chemotherapeutic agents [44,45,54]. However, the study by
Burnand et al., which used 90 mg of thiotepa in 100
mL rather than 30 mg in 50 mL (as in the MRC
study), found that 1 instillation of thiotepa significantly reduced the percent of patients who recurred,
as did Zincke et al. who used 60 mg of thiotepa in 60
mL [40,55]. This suggests that a lower concentration
of thiotepa may be responsible for the lack of efficacy. However, results from these 2 additional studies
should be interpreted with caution.
9. PRECAUTIONS
If there is a possibility of perforation or after an
extended TUR, an immediate instillation should not
be given. In case of the possibility of intraperitoneal
leakage or significant resorption from the extravesical space, it seems advisable not to use a dose which
is greater than the dose which is acceptable as 1 single intravenous injection. Indeed, 1 case of myelosuppression has been described when 80 mg of
MMC was retained for 2 hours after TUR of a large
tumor [66]. Nevertheless, it is clear from the review
of the literature that 1 immediate instillation after
TUR is an adjuvant treatment that adds hardly any
morbidity to the operation itself. Nearly all patients
already have a catheter after TUR and, if local
regional anesthesia is used, patients will not experience any additional discomfort. The reluctance to
use this treatment strategy should be reconsidered
since the potential benefits clearly outweigh the possible risks and costs.
7. COST-EFFECTIVENESS
Looking at initial recurrences only, 11.7 TURs were
saved for every 100 patients treated. Thus, the number needed to treat to prevent 1 recurrence is 1/0.117
= 8.5. Since the cost of a TUR, anesthesia, and hospitalization is probably more than 8.5 times the cost
of 1 instillation in most countries, a single instillation
should be cost-effective.
8. TOXICITY
Despite the fact that no serious adverse effects have
been mentioned in the trials published on immediate
adjuvant chemotherapy instillations, several reports
147
therapy until the first follow-up cystoscopy. Those
patients experiencing a recurrence, especially at multiple sites, at the first follow-up have an increased
risk of recurrence and could be selected for this therapy (Level 1/2, [47]). Using these prognostic factors,
patients at high risk for recurrence can be identified
and therapy could be applied as follows: a) one single instillation for patients with good prognostic factors and b) further instillations for patients with prognostic factors associated with a high recurrence rate.
VI. FURTHER INTRAVESICAL
CHEMOTHERAPY
According to a recent meta-analysis, a single immediate instillation of a chemotherapy agent significantly reduces the recurrence rate in patients included in a low risk group (Level 1, [54]). This might be
considered as the standard treatment for these
patients, but the question is whether this approach is
enough for patients at higher risk of recurrence or
whether patients need further adjuvant intravesical
chemotherapy.
1. DOSE AND SCHEDULE
In cases where more than a single instillation is needed, the question is what schedule should be recommended ? In the literature, there are no trials
designed for this specific group, but there are many
defined for low- to intermediate-risk groups, from
which one can extrapolate the results. In European
series comparing different chemotherapy agents in
patients stratified to low- and intermediate-risk
groups there is no superiority of any one agent
[61,62, Level 2; 71-73, Level 1].
Analyzing the Kaplan-Meier curves of 2 randomized
series with long-term follow-up demonstrated that
the effect of an immediate single instillation of
chemotherapy occurred during the first or second
year (Level 2, [49,51]). After this period, the curves
run parallel and tumor relapses occur in a similar
proportion in both the therapeutic and the observation arms. This means that after this period patients
are at risk of recurrence according to the natural history of the tumor, regardless of the initial benefit of
a single instillation. In a pooled analysis of 5 randomized trials, Hinotsu et al. observed that the effect
of intravesical chemotherapy essentially occurred
during the early phase of the recurrence (before 500
days), but the effect was no longer observed after this
period (Level 1, [67]). This trend was also observed
in patients with TaG1 or G2 tumors and was particularly remarkable in the TaG2 category according to
the higher recurrence rate than TaG1 in short and
long-term follow-up. Also, in a series by Tolley et al.
including low- and intermediate-risk groups, patients
receiving more than 1 single instillation of MMC had
a reduction in the recurrence rate compared with
patients who only received a single instillation (Level
2, [70]). In the meta-analysis from Sylvester et al.,
patients with multiple tumors had a recurrence rate
significantly lower than that of the control group but
significantly higher than patients with solitary
tumors (Level 1, [54]) . In consequence, the need of
more than one early instillation might be related to
prognostic factors for recurrence. In multivariate
analysis many prognostic factors have been identified as predictors or recurrence, but in this specific
group, multifocality, previous recurrence rate or
early recurrence, and size seemed to be the most relevant (Level 1, [47, 67]) .
There is more controversy regarding what is the most
suitable schedule for intravesical chemotherapy. Two
combined trials from the EORTC defined that
administration for longer than 6 months did not
improve the recurrence rate when the instillation was
administered early (Level 2, [61]). This observation
was confirmed by Nomata et al., who achieved a
recurrence-free rate of 55.1% and 48.5% at 3 years in
patients treated with 5 months or 1 year of epirubicin, respectively, with no significant difference
between the 2 arms (Level 2, [74]). Another randomized trial of 150 patients using early instillation
reported a lower recurrence rate after 1 year of treatment with epirubicin (19 instillations) compared to a
treatment of only 3 months (9 instillations) (Level 3,
[75]). Consequently, when early instillation of
chemotherapy is administered, a long course of
maintenance, more than 1 year, is not necessary, but
the suitable duration and number of instillations are
not well-defined.
The doses of each chemotherapy agent are not wellestablished, because they were decided empirically,
but in the literature there is a suitable range for each
one: doxorubicin 20 to 50 mg, epirubicin 20 to 100
mg, thiotepa 30 to 90 mg, and MMC 20 to 60 mg.
MMC 40 mg, epirubicin 50 mg, doxorubicin 50 mg,
and thiotepa 60 mg in 50 mL of physiologic solution
are most widely used. However, recently the need to
adapt the urinary pH for each agent was stressed
[77]. A prospective, double-armed, randomized,
As the progression risk is very limited in these
patients, one option is to start secondary instillation
148
these patients are treated in local hospitals and rarely
referred to academic centers. Therefore, there are
only a few reports dealing specifically with this
group of patients. Within this group of patients, progression is a rare event, but recurrence remains a
problem even in the best prognostic groups of
patients with TaG1 tumors or PUNLMP.
multi-institutional phase III trial with the aim to test
whether enhancing the drug’s concentration in urine
would improve its efficacy has been reported (Level
2, [77]). Patients in the optimized treatment arm
received a 40 mg dose of MMC with pharmacokinetic manipulation to increase drug concentration by
decreasing urine volume and urine alkalinization to
stabilize the drug. Patients in the standard treatment
arm received a 20 mg dose without any additional
manipulation. Patients in the optimized arm showed
a longer median time to recurrence and a greater
recurrence-free fraction at 5 years than patients in the
standard treatment arm. This pivotal study proved
the feasibility and efficacy of optimizing intravesical
chemotherapy.
2. THE ROLE
GUÉRIN)
OF
Holmäng et al. noticed 71% recurrences at 5 years
follow-up of TaG1 bladder tumors (Level 2, [1]).
Haukaas et al. described a single institution experience in 68 patients with TaG1 tumors; 40% of the
patients experienced a recurrence within 3 years
(Level 3, [84]) . Holmäng et al. have evaluated recurrence and progression patterns of patients with TaG1
lesions to whom intravesical therapy was rarely
administered (Level 3, [1]). The recurrence rate was
much higher in patients with multiple tumors.
BCG (BACILLE CALMETTE-
a) Papillary Urothelial Neoplasms of Low
Malignant Potential (PUNLMP)
Overall, in a systematic literature overview BCG significantly reduces the recurrence rate compared to
chemotherapy [79, Level 2; 80, Level 1]. However,
concerning the intermediate- to low-risk group, this
evidence is not clear. In 2 recent meta-analyses, BCG
was not superior to MMC except for patients previously treated with intravesical chemotherapy (Level
1, [81]). However, BCG significantly reduces recurrence and progression in high-risk patents [82, Level
2; 83, Level 1]. Concerning low- to intermediate-risk
groups, in another meta-analysis BCG was not superior to MMC unless maintenance was applied (Level
1, [83]). However, all 3 studies with patients at intermediate risk included in this meta-analysis were not
randomized trials and did not have homogeneity statistical tests applied. In addition, 1 study was published in abstract form and other methodological
problems were observed. In summary, there is no scientific evidence that in the intermediate-risk group
BCG is superior to intravesical chemotherapy, even
if BCG maintenance is administered. On the other
hand, in all series BCG was significantly more toxic
than intravesical chemotherapy. In consequence, in
patients with TaG1 or G2 tumors at high risk of
recurrence, BCG should not be used as first-line
treatment but can be used as a second-line therapy.
In patients with PUNLMP, there were 35% recurrences at 5 years in 95 cases. More recently, Fujiï et
al. evaluated 53 patients with PUNLMP, followed for
at least 5 years, and detected a 66% recurrence rate
(Level 3, [4]) . At 2, 5, and 10 years, the recurrence
rates were 66%, 52%, and 36%, respectively.
No patients developed higher grade, muscle-invasive
tumors or upper urinary tract tumors in the abovementioned studies. But despite the low malignant
potential of these tumors, there is still a high and
long-lasting chance for recurrence.
b) Recurrence in Low Grade pTa Tumors
Many studies have examined several clinical factors
that predict recurrence.
1. MULTIPLICITY
Multiplicity of the tumor was found to be predominant in prediction of recurrence in all identified studies examining this issue [1,34,68,85,86, Level 2;
72,83, Level 1; 87,88, Level 3]. The recurrence risk is
nearly twice as high when more than a single tumor
is present.
In the study by Prout et al. of 187 patients with a
mean follow-up of 58 months, the recurrence rate
was 90% for patients with multiple tumors and 46%
for patients with single lesions (Level 2, [89]).
VII. PROGNOSTIC FACTORS AND
FOLLOW-UP
2. RECURRENCE AT 3-MONTH CYSTOSCOPY
This was another factor which was studied by several investigators but not specifically in TaG1 tumors
[69,86,90,91, Level 2; 87, Level 3]. All investigators
found a strong correlation with later recurrence.
1. PROGNOSTIC FACTORS
Noninvasive low grade Ta bladder tumors account
for 25% to 50% of bladder carcinomas. Most of
149
3. PREVIOUS RECURRENCE RATE
In conclusion, evolution to higher grade and stage in
TaG1 tumors does occur, but in less than 20% of the
cases. Evolution to progression is a rare event.
A recurrence rate of more than one per year was also
found to be a prognostic factor for recurrence
[34,68,90 Level 2; 72, Level 1]. This finding coincides with that of a higher overall recurrence rate
when tumor is identified at 3 months.
a) Frequency of Cystoscopy
Many authors suggested to diminish the heavy
schedules of cystoscopy used in the past and to adapt
them to the risk factors mentioned above. However,
there are rare data which calculate the risk at any
given surveillance schedule. Based on their experience in 120 papillary G1 and G2 tumors, Oge et al.
proposed to postpone cystoscopy for another 9
months in those cases where the first cystoscopy at 3
months is negative [96].
Hazard function studies can help the decision on cystoscopy schedules. In an analysis of 1732 patients
with all types of superficial bladder tumors, Hinotsu
et al. found an earlier peak of recurrence in multiple
and recurrent tumors than in single ones when no
prophylactic treatment was given (Level 1, [67]). The
early phase recurrence (within 200 days) is
decreased by intravesical chemotherapy while late
recurrence after 500 days seems not to be influenced.
b) Duration of Follow-up
All studies in which patients were followed over a
long period mention recurrence even after several
years of follow-up with no disease. A risk of recurrence remains lifelong, but most experts propose to
stop cystoscopic surveillance when it remains negative for 5 years.
4. SIZE OF THE TUMOR
Milan-Rodriguez et al. reported that the risk at recurrence was 1.6 times higher for patients with a tumor
greater than 3 cm, as previously reported [72, Level
1; 89, Level 2; 92].
5. GRADE AND T STAGE
Although of value, these are of less importance in the
prediction of recurrence than the above-mentioned
factors. Grade and stage have, however, a major
impact on the chance of progression.
6. PROGRESSION
In the above-mentioned studies, no progression was
noticed for the group of patients with PUNLMP, and it
has been rarely described in other series (Level 3, [93]).
2. FOLLOW-UP
Patients with TaG1 tumors should be followed,
although the expected risk of recurrence as well as
the risk of progression to a muscle-invasive disease
is very low and early detection of recurrence is not as
important as it is for superficial bladder tumors with
a higher grade. As elucidated above, the most important factors are multiplicity, recurrence at 3 months,
previous recurrence rate, and size of the tumors
(greater than 3 cm).
VIII. OFFICE FULGURATION OF
RECURRENT LOW GRADE Ta
TUMORS
Evolution to a higher grade can occur. Borhan et al.
found an evolution to a higher grade in 179 TaG1
tumors in 29 cases (16.3%) ; 5 progressed to grade 2
and 24 to grade 3 (Level 3, [94]). Only 5 progressed
to T1 and 3 to muscle-invasive disease. Holmäng et
al. saw a 2.4% progression rate to muscle-invasive
disease [1]. Leblanc et al. noted 21 progressions to
G2 or G3 and 3 to CIS in a total of 152 TaG1 tumors
with a follow-up from 6 to 241 months (mean 76
months) (Level 3, [93]). Thus, 17% evolved to a
higher grade and of them 5 developed muscle-invasive disease (3.3%). Borhan et al. reported a grade
progression in 11% of 82 TaG1 and G2 tumors
(Level 3, [94]). Soloway et al. followed 32 patients
with low grade tumors for a mean period of 38
months and noted that the tumor growth per month
was approximately 1.77 mm [95]. Only 3 patients
developed a higher grade or stage.
The majority of patients (75%-80%) with newlydiagnosed bladder cancer present with noninvasive
disease. Approximately half of these patients present
with low grade lesions, now classified according to
the WHO International Society of Urologic Pathology as low grade papillary tumors (TaG1) or papillary
urothelial neoplasms of low malignant potential.
Such tumors have traditionally been managed with
TUR with or without immediate bladder instillation
of a chemotherapeutic agent such as MMC. In an
attempt to minimize the need for TUR and reduce the
cost of hospitalization and anesthesia, several
authors have investigated the feasibility and efficacy
of outpatient fulguration of cystoscopically-appearing low grade, noninvasive recurrent papillary
tumors of the bladder.
150
1. FEASIBILITY
ration. Patients who had positive urine cytology
underwent formal biopsy.
The feasibility of fulguration or ablation of bladder
tumors via flexible cystoscopy has been confirmed in
multiple studies. German et al., using topical local
anesthetic gel, found that only 2 of 17 (12%) patients
described the procedure as painful (Level 3) [97].
Dryhurst et al. further refined the anesthetic technique by instilling a 60 mL solution of lidocaine
retained in the bladder for 20 min prior to fulguration
(Level 3) [98]. Syed et al. described the use of the
Holmium:Yag laser for tumor ablation via a flexible
cystoscope under local anesthesia (Level 3) [99]. In
that study, 83% of patients scored their pain as 2 or
less out of 10 on a visual analog scale.
Of the 267 patients, 103 underwent office fulguration at least once during the study period, although
only 74 of 123 (60%) were managed by fulguration
alone. Patients who underwent fulguration were at
no greater risk of disease progression or cancer death
than those who never underwent fulguration and
were managed by TUR of tumor alone.
The authors concluded that office fulguration is
appropriate for selected patients with recurrent low
grade superficial urothelial carcinoma of the bladder.
Summary
2. EFFICACY
In summary, there is sparse prospective data
regarding the efficacy of fulguration alone in the
management of recurrent bladder lesions. However, an extensive experience from the Memorial
Sloan-Kettering Cancer Center suggests that in
selected patients with less than 5 small (<0.5 cm)
low grade-appearing recurrent tumors and negative urine cytology, office fulguration alone is
safe and effective. All authors concur that office
fulguration alone is inappropriate for initial management of a bladder lesion.
Herr evaluated the efficacy of outpatient fulguration
of papillary lesions of the bladder. In this study,
patients with a history of both low grade and high
grade invasive lesions, some of whom had received
BCG, were included (Level 3) [100]. All patients
were either tumor-free or had a noninvasive recurrence in the 6 months prior to inclusion. A total of 69
patients underwent office fulguration. Of these, 47
(68%) were managed with fulguration alone. Of 22
patients who required TUR, 3 had muscle-invasive
disease and 5 had CIS. Of 34 patients who required
repeated fulguration, the tumor recurred at the site of
prior fulguration in 10 (30%). The procedure was
well-tolerated.
IX. URINE CYTOLOGY AND URINEBASED MARKERS IN LOW GRADE
TA UROTHELIAL CARCINOMA OF
THE BLADDER
In a prospective study, Wedderburn et al. evaluated
the efficacy and tolerance of outpatient fulguration in
103 patients with a history of recurrent TaG1 tumors
(Level 3) [101]. Median follow-up was 21 months.
Half of the patients (52/103) had no recurrence following fulguration. In 13 (13%) patients, recurrences
occurred either at or close to the site of the original
fulguration. Discomfort was mild or negligible for
80% of the patients.
The diagnosis of a papillary superficial bladder cancer (pTa) comprises 2 discrete entities: low grade
innocuous lesions and high grade, potentially lethal
tumors. These 2 entities vary considerably in appearance, risk and pattern of recurrence, and their biologic propensity to ultimately progress. Although
high- and low-risk groups in superficial bladder cancer have been described, clinical or pathological
prognostic factors cannot predict progression on an
individual basis (Level 2, [103]). Therefore, other
criteria for identifying patients with a high risk for
progression, as well as the identification of “markers” that define tumors that are likely to respond (or
not) to specific therapeutic regimens, need to be
defined and validated. Only this will provide a basis
for patient-specific treatment decisions that better
reflect the biology of individual tumors.
Donat et al. recently presented a prospective analysis
of 267 consecutive patients with a history of urothelial carcinoma of the bladder who underwent routine
surveillance cystoscopy over a 4-year period (Level
3) [102].
These included 238 (89%) with an initial tumor of
stage T1 or less and 25 (9%) who presented with a
muscle-invasive tumor. All patients had subsequently been tumor-free for 6 months following TUR of
their initial tumor. Patients with low grade-appearing
and fewer than 5 recurrences, all of which were less
than 0.5 cm in diameter, were considered for fulgu-
151
identification of Ta tumors. Thus, urine-based markers may be of interest as a beneficial adjunct to urine
cytology. In addition, combining markers may
increase their predictive or prognostic value. Comprehensive approaches determining the right combination are awaited and should include the effects on
specificity.
Established factors used to identify patients with a
higher risk of tumor recurrence or progression
include initial tumor stage and grade, number of initial tumors (multifocality), size of initial lesion, presence of associated CIS, early recurrence, stage
migration, and response to therapy. Current surveillance schedules are more or less individualized based
on these factors. These hallmarks of current risk
assessment are the ones against which cytology or
urine-based markers need to be compared when evaluating their role and potential.
In case malignant cells are available, cytology has
been shown to have the best specificity, and only a
few urine-based markers have been shown to yield
comparable results (Level 2, [104,108]). Thus, most
of the urine-based markers demonstrate higher false
positive rates compared to urine cytology (Level 2,
[104,108], Level 3 [109]). Besides the fact that in
most studies patients had lesions of lower grade or
may have already been treated, the presence of microhematuria or concomitant urinary tract infection may
have contributed to these results. Although from an
economic standpoint many of the current available
tests may be superior to cytology, not all can be considered as point-of-care techniques, since some
require technical expertise not available in many
institutions (Level 2, [110,111]). In addition to these
disadvantages, some of these tests have exclusion criteria limiting their clinical use and a consensus on
cut-off values or test performance has not yet been
reached.
The role of urine cytology and urine-based markers are discussed here with the focus on low grade
papillary tumors. A more comprehensive
overview on this topic is provided in Chapters 1
and 2.
1. INITIAL TUMOR GRADE
Although the evaluation of urine samples containing
tumor cells (urine cytology) has much improved over
the recent years, in clinical practice urologists still
rely on cystoscopy to detect bladder cancer (Level 2,
[104]). Due to low cellular yields, atypia, and degenerative changes or alterations of the mucosa caused
by therapy, interpretation of cytology can be problematic (Level 3, [105]). Various methods are used to
obtain shed cells, including voided urine cytology,
bladder washings, catheterized urine, and the THINprep method. It is also not common practice to obtain
multiple sequential samples for urine cytology prior
to any definite judgment. This may have an influence
of uncertain magnitude on the reliability of the
results. In addition, evidence-based guidelines on the
performance of urine cytology are missing in the literature, and although the educational process over
the recent years has much improved, the interpretation is still subjective, which makes comparison of
results difficult (Level 3, [106,107]).
Although there is considerable promising data on the
advantages of urine-based markers, and despite the
obvious disadvantages, especially for the detection of
low grade papillary lesions, urine cytology may still
remain the standard for bladder cancer screening.
However, for the determination of the initial tumor
grade, neither cytology alone nor any of the currently
available urine-based urinary markers can replace the
histopathological evaluation of resected tumor cells.
2. PRESENCE
SITU
As a recent meta-analysis confirmed, most of the
currently available urine-based markers (Table 2)
are more sensitive (with a median overall sensitivity
for all stages ranging from 20%-99%) than urine
cytology, which has a low median overall sensitivity
of 34% (Level 2, [108]). Another meta-analysis
showed similar results (Table 3) (Level 2, [104]).
This is especially of clinical interest for the detection
of low grade lesions (median overall sensitivity ranging from 2%-97%) and for Ta tumors (median overall sensitivity ranging from 12%-96%) (Level 2,
[108]). Urine cytology has a lower median overall
sensitivity ranging from 4% to 31% for the detection
of low grade lesions and from 9% to 25% for the
OF
ASSOCIATED CARCINOMA
IN
In the case of concurrent CIS or suspected upper urinary tract lesions, cytology may guide further evaluation (33, Level 1;37,112, Level 2). In addition, urine
cytology may identify high grade malignant cells
before they are identifiable cystoscopically. Thus,
random biopsies become necessary when there is
positive urinary cytology or when CIS is suspected.
In these instances, the role of urine cytology remains
important and urine-based markers may have a higher sensitivity (Table 2). However, it should be noted
that the total number of patients with CIS was low in
all studies (Level 2, [108]).
152
Table 2. Sensitivity of Various Urine-based Markers and Cytology [108]
Sensitivity (95% Confidence Interval)
pTa (%)
G1 (%)
CIS (%)
Overall (%)
Urine cytology
15 (9-25)
12 (4-31)
63 (29-87)
34 (20-53)
BTA test
33 (17-53)
32 (14-58)
50 (20-80)
49 (24-74)
BTA-Stat
57 (47-67)
47 (38-56)
73 (54-86)
71 (57-82)
NMP-22
60 (42-76)
61 (35-81)
66 (42-83)
73 (47-87)
BTA-TRAK
57 (31-80)
63 (27-89)
68 (44-85)*
69 (55-80)
FDP
56 (27-81)
42 (7-89)
65 (27-80)
77 (41-93)
Hgb dipstick
25 (12-44)
8 (2-48)
45 (12-83)
52 (27-76)
75
86 (40-97)
100
94 (74-99)
UBC (CK 8/18)
62 (41-79)
57 (21-86)
96 (3-99)
66 (50-79)
BCA (CK 8/18)*
58
70
67*
83 (55-95)
CK 20*
96
100*
91 (83-96)
99 (56-99)
77 (53-91)
87*
89 (67-97)
CYFRA 21-1 (CK 19)
Telomerase
HA*
74 (52-88)
61 (30-85)
77
Modified table according to Lotan and Roehrborn showing the median sensitivity by grade and stage and the overall median
sensitivity of urine-based marker tests based on the data of at least 2 independent studies. Asterisk (*) indicates that for these
studies the median sensitivity by grade and stage was based on the data of a single study.
Table 3. Sensitivity of Various Urine-based Markers and
Cytology [104]
frequent cystoscopies, the need for urine cytology or
the use of urine-based markers is debatable.
Overall Sensitivity
(95% Confidence Interval) (%)
A progression in tumor grade may help to identify
those patients at higher risk for progression (Level 2,
[4]). It is very unlikely that a high grade lesion is
missed by either urine cytology or most of the current available urine-based markers during follow-up
since their sensitivity has been proven to be even
slightly higher than the sensitivity of urine cytology
(Level 2, [108]). However, since the specificity of
urine cytology remains superior compared to urinebased markers, it may not be replaced in this scenario.
Urine cytology
55 (48-62)
BTA test
50 (30-65)
BTA-Stat
70 (66-74)
NMP-22
67 (60-73)
BTA-TRAK
66 (62-71)
Telomerase
75 (71-79)
3. URINARY MARKERS IN FOLLOW-UP
Summary
The aim of these tests is the detection of a recurrent
tumor. This leads to 2 different scenarios:
Urine cytology or urine-based markers need to be
evaluated in light of the established factors for risk
assessment. Urine cytology contributes to a very
limited extent to the determination of these factors,
limiting its importance for the management of low
grade papillary transitional cell carcinoma. Urinebased markers are needed to improve the predictive
and prognostic value of urine cytology in low
grade papillary disease, but there is currently no
evidence that they are sufficient to replace urine
cytology.
The detection of another consecutive low grade
lesion is of questionable value with regard to the
determination of disease progression and may have
low impact on the clinical management. Urine cytology, with its low sensitivity to detect these lesions,
plays only a minor role. Although promising, to date
ancillary tests performed to improve the sensitivity of
urine cytology have not been shown to be of additive
value. In addition, if the low likelihood of recurrence
and subsequent progression after a 10-year diseasefree follow-up interval leads to the discontinuation of
153
A pooled analysis of 11 case-control studies by Brennan et al. consisted of 2279 cases and 5268 controls
from various countries in Europe (Level 2, [116]). A
dose-response relationship was observed between
the numbers of cigarettes smoked per day and bladder cancer. However, this relationship was weaker
than that in lung cancer. Furthermore, an immediate
and significant decrease in the risk of bladder cancer
was also evident for those who quit smoking. This
study underscores the fact that, although 1 of every 3
cases of bladder cancer is attributable to past smoking history, another 1 of every 3 cases is due to current smoking. A 40% decrease in risk can be accomplished by smoking cessation. The overall risk of
bladder cancer for ever-smokers compared to neversmokers was 3.63 in this study.
In summary, neither urine cytology nor urinebased markers have been demonstrated to be of
sufficient value to replace cystoscopy in the diagnosis and follow-up of low grade superficial bladder cancer.
X. LIFESTYLE, DIET, AND FOOD
SUPPLEMENTS
As noninvasive bladder cancer is a disease with a
long history of development and dietary factors may
play a role, it is worthwhile to examine whether
advice on lifestyle, diet, or food supplements can be
provided to the patient.
Bladder cancer is relatively less frequent in females.
Pelucchi et al. investigated smoking habits specifically in females in a case-control study conducted in
Italy (Level 3, [117]). Compared to never-smokers,
ever-smokers and current smokers had odds ratios of
2.47 and 2.87, which were statistically significantly
different. Brennan et al. have analyzed the effect of
tobacco use on bladder cancer in females using the
pooled analysis of 11 European case control studies
(Level 2, [118]). Similarly to the previous study, the
overall risk of bladder cancer among women for
ever-smokers compared to never-smokers was found
to be 3.1. These studies show that the causal relationship between cigarette smoking and bladder cancer is independent of gender.
1. SMOKING
Smoking is one of the major causes of bladder cancer. Zeegers et al. performed a meta-analysis of 43
published case-control and cohort studies in the literature and analyzed the effect of tobacco use on bladder cancer (Level 1, [113]). The adjusted odds ratios
(OR) for current cigarette smokers compared to nonsmokers were 3.18 for studies with men, 2.90 for
studies with women, and 3.33 for studies of both
sexes. Although former smokers have a relatively
lower OR than current smokers, it is not significantly different, especially in men (OR 2.90 vs. 3.18).
Positive dose-response relationships were found
with both the number of cigarettes smoked per day
and the number of years smoked.
Though the causal relationship between cigarette
smoking and bladder cancer is well-established,
information about the carcinogenic effects of cigar
and pipe smoking is far from clear. In a pooled analysis of 6 case-control studies from Europe, this relationship was investigated (Level 3, [119]). The relative risk of bladder cancer for smoking any kind of
tobacco product was 3.5 compared to nonsmokers.
Although cigarette smoking was associated with the
highest risk, pipe and cigar smoking had odds ratios
of 1.9 and 2.3, respectively. However, a more extensive and recent study has shown that cigar smoking
has no effect on the risk of bladder cancer (Level 3,
[120]). The amount of tobacco consumed and the
duration also correlated with the risk of bladder cancer development in cigarette smoking but not in pipe
or cigar smoking.
Zeegers et al. systematically reviewed the effects of
smoking on bladder cancer based on previous literature and specifically on the results of the ongoing
Netherlands Cohort Study (114, Level 2; 116, Level
3). They used a rating system to summarize the level
of scientific evidence for risk factors as convincing,
probable, possible, and no evidence. Based on these
criteria, the authors have concluded that cigarette
smoking substantially increases the risk of developing bladder cancer. Cigarette smoking duration is the
major determinant for bladder cancer development
risk independent of differences in tumor invasiveness or morphology. Though cigar and pipe smoking
substantially increased the risk of bladder cancer
development, these risks disappeared after adjustment for cigarette smoking. It was also found that
total smoking duration is much more important than
cessation of smoking and age at first exposure (Level
3, [115]).
Fleshner et al. showed that although current smoking
has an adverse impact on recurrence and progression, there was no difference noted between former
smokers and those who quit after diagnosis (Level 3,
154
of low vitamin A intake was 1.10 and thus the
authors failed to show a significant impact of dietary
Vitamin A. Michaud et al., in the Health Professionals Follow-up Study, also showed that dietary intake
of vitamin A was not associated with bladder cancer
risk (RR 0.97) (Level 2, [126]).
[121]). This finding contradicts with the aforementioned studies. Although consensus has been reached
on the adverse effect of current smoking, extensive
studies are needed to clarify whether cessation of
smoking at diagnosis is beneficial as well.
2. FLUID INTAKE
Moreover, neither duration nor dose of vitamin A
intake was associated with bladder cancer risk.
Zeegers et al., in their systematic review, also
reached the conclusion that vitamin A had no association with the risk of bladder cancer (Level 3, [115]).
In a prospective study of 47 909 men, a high intake
of fluids was associated with reduced risk of bladder
cancer after control for potential risk factors (Level
2/3, [122]). Study participants in the highest quintile
of fluid intake had a 49% lower incidence of bladder
cancer than those in the lowest quintile. However,
according to one prospective non-randomized study
(Level 3, [123]), a multicenter case-control study
(Level 3, [124]) and a systematic review (Level 2,
[114]) of the literature, there was no reduction in risk
with high fluid intake.
A multicenter, prospective, randomized, doubleblind study on the effect of vitamin A analogue on
the recurrence rate of patients with superficial bladder cancer recruited 79 eligible patients (Level 2,
[128]). Although recurrence rates decreased significantly with vitamin A analogue treatment, early
withdrawal of a significantly greater number of
patients in the placebo arm and side effects in the
treatment arm have hampered the validity of the
results.
3. FRUITS AND VEGETABLES
A meta-analysis of 7 case-control studies and 3
cohort studies performed by Steinmaus et al. showed
that a small elevated bladder cancer risk exists in
patients with low fruit consumption versus those
with high fruit consumption (relative risk [RR] 1.5)
after adjusting for smoking (Level 2, [125]). In the
same meta-analysis, a less convincing relationship
was also reported on the effect of high vegetable
consumption (RR 1.2)
5. VITAMIN C
In the Health Professionals Follow-up Study, dietary
vitamin C was found to have no association with
bladder cancer risk (Level 2, [127]). Although vitamin C supplement use for more than 10 years was
associated with a significant reduction in bladder
cancer risk (RR 0.83), the significance disappeared
after adjustment for smoking. The Netherlands
Cohort Study reported by Zeegers et al. also confirmed the aforementioned observations, which
showed that neither dietary nor supplementary vitamin C had any association with the risk of developing bladder cancer (Level 2, [114]).
The Health Professionals Follow-up Study, which is
a prospective cohort study reported by Michaud et al.
involving 47 909 men, investigated the effect of total
fruit and vegetable intake on bladder cancer development, but failed to show a significant relationship
after adjustment for smoking (Level 2, [126]).
Zeegers et al. also reported an inverse association
between bladder cancer and fruit intake comparing
the highest and lowest quintile of total fruit consumption (RR 0.7) (Level 2, [114]). There was no
association between vegetable intake and risk of
bladder cancer development in the same study (RR
0.9).
6. VITAMIN E
Vitamin E may have a role in maintaining selenium
in its reduced state and inhibiting nitrosamine formation in the gut. The Health Professionals Follow-up
Study reported by Michaud et al. found a reduced
risk of bladder cancer with a high total intake of vitamin E (Level 2, [127]). Subjects who took vitamin E
supplements for more than 10 years had a reduction
of 30%. In this study, both dietary intake of total
vitamin E and vitamin E supplement use decreased
the risk of bladder cancer. In multivariate models,
current use of vitamin E supplements was inversely
associated with bladder cancer risk (RR 0.70). A
cohort derived from the Cancer Prevention Study II
reported by Jacobs et al. demonstrated the relation-
There is possibly no association between total vegetable consumption and bladder cancer development
(Grade B).
4. VITAMIN A
Steinmaus et al. performed a meta-analysis of epidemiological studies linking retinol and carotenoids
to bladder cancer (Level 2, [125]). The relative risk
155
ences in favor of Lactobacillus casei, however,
became only statistically significant when a Cox
multivariate analysis was performed (Level 3,
[132]).
ship between vitamin E supplements and bladder
cancer mortality (Level 3, [129]). In this large cohort
of US men and women, regular long-term use of
vitamin E supplements was associated with a
reduced risk of bladder cancer mortality.
The inhibitory effect of Lactobacillus casei on bladder tumors was investigated in an experimental
model of nitrosamine-induced rat bladder cancer
[133]. Tumor volume was lower in Lactobacillus
casei-treated rats, and this was more pronounced
with a longer duration of treatment. The degree of
malignancy of the induced tumors was significantly
lower in the treated group.
However, Zeegers study of the Netherlands cohort
failed to show this relationship (Level 3, [115]).
7. VITAMIN B
Newling et al., in an EORTC study, have reported
that pyridoxine administration to patients with Ta
and T1 tumors had no effect on recurrence rates
when compared to placebo (Level 1, [130]). Furthermore, these negative results did not change with
adjustment to various prognostic factors.
In an epidemiological study (case-control), a total of
180 cases and 454 population-based controls were
selected. The odds ratio for those who had an intake
of Lactobacillus casei by drinking fermented milk
products was 0.46 for 1 to 2 times per week and 0.61
for 3 to 4 or more times per week. This suggest that
the habitual intake of Lactobacillus bacteria may
reduce the risk of superficial bladder tumors [134].
8. VITAMIN COMBINATIONS
Lamm et al. studied the effect of a megadose vitamin
combination in a double-blind randomized trial
(Level 1, [131]). A total of 65 patients with biopsyconfirmed urothelial carcinoma of the bladder were
randomized to receive the recommended daily
allowance of multiple vitamins or a megadose of
vitamins A, B6, C, and E plus 90 mg of zinc. There
were no significant differences in known risk factors
between the groups. However, stratifying the cases
according to tumor stage revealed a statistically significant 42% reduction in tumor recurrence for
superficial (Ta, T1) and 53% reduction for low grade
(G1, G2) urothelial carcinoma in favor of patients
receiving megadose vitamins. The high dose vitamins were generally well-tolerated, with mild nausea
being the most common side effect. This combination of potentially therapeutic agents was low in toxicity and expense.
The supposed mechanisms of its action are detoxication of chemical carcinogens and activation of the
immune system. Additionally, there is anti-tumor
effect demonstrated of intravesical instillation of
heat-killed cells of Lactobacillus casei on the murine
orthotopic bladder tumor MBT-2 [135].
9. LACTOBACILLUS CASEI AS A PROPHYLACTIC
AGENT FOR RECURRENCE OF SUPERFICIAL
BLADDER TUMORS
In a multicenter, prospective, randomized doubleblind trial, 139 patients with superficial bladder
tumors following TUR were included to evaluate the
prophylaxis of recurrence by an oral Lactobacillus
casei preparation in comparison to placebo (Level 3,
[132]). Efficacy could be evaluated in 61 patients of
the Lactobacillus casei group and in 64 in the placebo group. In primary, multiple tumors and recurrent,
single tumors, Lactobacillus casei showed a better
prophylactic effect than placebo. When given in
recurrent, multiple tumors, which were at higher risk
for recurrence, there was no difference. The differ-
156
RECOMMENDATIONS
II. ACCURACY OF CYSTOSCOPY IN
DEFINING PAPILLARY TUMORS
reduce the recurrence rate by about 40% in single as
well as in multiple superficial bladder tumors and
thus is recommended for all types of papillary superficial bladder cancer (Grade A).
1. Cystoscopy in experienced hands is accurate in identifying recurrent low grade tumors that are characterized by the absence of the following features
(Grade B).
2. The doses of 40 mg MMC and 50 mg epirubicin in
50 mL are most widely advocated. Higher doses
increase the risk for side effects without increasing
efficacy (Grade B).
2. Lesions with the following characteristics should be
evaluated by biopsy (Grade B):
3. After extensive resection and in the case of obvious
or suspected perforation of the bladder wall, it is
prudent not to instill a chemotherapeutic agent as
extravasation can provoke annoying and even dangerous complications (Grade D).
Greater than 0.5 cm in diameter
Areas of nodularity
More than 5 lesions present
Positive urine cytology
4. It is advocated to give the instillation the same day of
the TUR as it is probably insufficient the day afterwards (Grade B) .
Lesions in patients not yet diagnosed with bladder
cancer
5. Further adjuvant intravesical therapy is indicated in
multiple tumors as 1 single instillation is an insufficient treatment (Grade A).
III. UPPER URINARY TRACT
EXPLORATION IN LOW GRADE TA
UROTHELIAL CARCINOMA OF
THE BLADDER
VI. FURTHER INTRAVESICAL
CHEMOTHERAPY
1. The diagnostic exploration of the upper urinary tract
in patients with Ta G1 or G2 bladder tumors is not
recommended at initial diagnosis or during followup (Grade B).
1. Secondary intravesical therapy should be given in
patients with low grade Ta tumors when high risk
factors for recurrence are associated. Secondary
intravesical therapy can be administrated initially in
a standard approach or to patients with multiple
recurrences at first follow-up cystoscopy (Grade C).
2. Symptomatic patients or those with positive urinary
cytology in the absence of bladder tumors should
undergo upper urinary tract exploration (Grade A).
2. Intravesical chemotherapy is recommended as a firstline treatment, and the duration of treatment should
be less than 6 months (Grade B).
IV. PRIMARY TREATMENT OF LOW
GRADE TA UROTHELIAL CARCINOMA OF THE BLADDER
3. Intravesical BCG should be reserved for second-line
treatment (Grade A).
1. Urinary cytology is recommended prior to initial
TUR for the diagnosis of bladder cancer because, if
it is positive, random biopsies have a higher chance
to detect CIS of the bladder and a high grade tumor
is more likely to be present (Grade A).
VII. PROGNOSTIC FACTORS AND
FOLLOW-UP
1. Although the chance of progression is very low in
TaG1 tumors, the number of recurrences remains
high and is long-lasting (Grade B).
2. If cytology does not show malignant cells and the
lesion has a papillary structure, random biopsies are
not indicated. Traumatized bladder mucosa may
enhance implantation of tumor cells (Grade B).
2. Number and size of tumors are the most important
prognostic factors in TaG1 tumors (Grade B).
Recurrence at the first surveillance cystoscopy or a
previous recurrence rate of more than 1 per year is
also an important prognostic factor (Grade B).
3. A second resection is not useful in low grade Ta
lesions (Grade B).
V. ONE EARLY PERIOPERATIVE
INSTILLATION OF
CHEMOTHERAPY
3. A cystoscopy is advocated at 3 months. If negative,
the next cystoscopy can be postponed for 9 months
(Grade C).
1. Instillation with MMC (MMC) or epirubicin can
157
VIII. OFFICE FULGURATION OF
RECURRENT LOW GRADE TA
TUMORS
X. LIFESTYLE, DIET, AND FOOD
SUPPLEMENTS
1. Cigarette smoking increases the risk of bladder cancer threefold (Grade A).
1. Office fulguration alone is not appropriate treatment
of an initial bladder tumor (Grade C).
2. Current smokers have increased adverse outcomes
compared to nonsmokers (Grade B).
2. In selected patients with less than 5 small (<0.5 cm)
low grade-appearing recurrent tumors in the setting
of negative urine cytology, office fulguration is
appropriate (Grade C).
3. The risk increases with the number of cigarettes
smoked per day (> 20) and the number of years (>
20) as a smoker (Grade C).
3. Whenever there is clinical doubt whether a tumor is
low grade, if urine cytology is positive, or if there
appears to have been a change in the appearance of
tumors, formal TUR is necessary (Grade C).
4. The favorable effect of quitting smoking after diagnosis of bladder cancer is probable, but not clearly
proven (Grade C).
IX. URINE CYTOLOGY AND URINEBASED MARKERS IN LOW GRADE
Ta UROTHELIAL CARCINOMA OF
THE BLADDER
6. There is a probably a slight inverse relationship
between total fruit intake and risk of bladder cancer
development (Grade B).
5. There is possibly no association between total fluid
intake and risk of bladder cancer (Grade B).
7. Vitamins A, B6, and C have no association with the
risk of bladder cancer (Grade B).
1. To define a low grade papillary tumor, neither urine
cytology nor urine-based markers are needed (Grade
A).
8. A probable moderate inverse relationship between
vitamin E supplement use and bladder cancer risk
may be present (Grade C).
2. Urine cytology has its role for the detection of concurrent CIS or high grade malignant cells prior to
cystoscopy. Thus, random biopsies become necessary when there is positive urinary cytology or when
CIS is suspected (Grade B).
9. Lactobacillus casei may have a protective effect on
recurrence of superficial bladder tumor (Grade C).
3. Urine cytology or the use of urine-based markers
should not be used for the follow-up of well-defined
low grade lesions with their low liability to progress
(Grade B).
158
159
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163
164
Committee 4
High Grade Ta Urothelial
Carcinoma and Carcinoma in Situ of
the Bladder
Chairs
R. SYLVESTER (BELGIUM)
A. V.D. MEIJDEN (NETHERLANDS)
Members
J.A. WITJES (NETHERLANDS)
G. JAKSE (GERMANY)
N. NONOMURA (JAPAN)
C. CHENG (SINGAPORE)
A. TORRES (MEXICO)
R. WATSON (AUSTRALIA)
K.H. KURTH (NETHERLANDS)
165
CONTENTS
3. DIAGNOSIS OF CIS
I. HIGH GRADE Ta UROTHELIAL
CARCINOMA
4. PROGNOSIS
1. DEFINITION AND CHARACTERISTICS
5. PROGNOSTIC FACTORS
CIS
2. INCIDENCE
6. TREATMENT OF CIS
IN
PATIENTS
3. DIAGNOSTIC WORK-UP
RECOMMENDATIONS
4. PROGNOSIS
5. TREATMENT
ALGORITHM 1
ALGORITHM 2
II. CARCINOMA IN SITU
REFERENCES
1. DEFINITION AND CHARACTERISTICS
2. INCIDENCE
166
WITH
High Grade Ta Urothelial Carcinoma and
Carcinoma in Situ of the Bladder
R. SYLVESTER, A. V.D. MEIJDEN
J. A. WITJES, G. JAKSE, N. NONOMURA, C. CHENG, A. TORRES, R. WATSON, K. H. KURTH
Table 1. Incidence of High Grade Ta Bladder Cancer
I. HIGH GRADE Ta UROTHELIAL
CARCINOMA
Reference
Among Ta
Tumors
Among Ta or
T1 Tumors
1. DEFINITION AND CHARACTERISTICS
Chen [6]
14/140 (10.0%)
Haukaas [7]
5/140 (3.6%)
5/231 (2.2%)
The most recent TNM Classification of Malignant
Tumors, the 6th edition, was published by the International Union Against Cancer in 2002 [1]. Ta
tumors are defined here as noninvasive papillary carcinomas, those that do not invade the subepithelial
connective tissue (lamina propria).
Heney [8]
5/175 (2.9%)
5/249 (2.0%)
A number of different tumor grading classification
systems have been published, including the 1973
WHO [2], the 1998 WHO/ISUP [3], and the 1999
WHO [4]. Here, high grade refers to grade 3 tumors
defined according to the widely used 1973 WHO
classification system. There is evidence (Level 3)
that the high grade group based on the 1998
WHO/ISUP classification is composed of 2 subgroups with different marker profiles and prognoses
corresponding to 1973 WHO grades 2 and 3 [5].
Lutzeyer [14]
Holmang [9]
9/77 (11.7%)
9/176 (5.1%)
Holmang [5,10]
13/363 (3.6%)
13/481 (2.7%)
Jakse [11]
16/89 (18.0%)
16/172 (9.3%)
Larsson [12]
15/292 (5.1%)
15/402 (3.7%)
Lebret [13]
32/605 (5.3%)
9/270 (3.3%)
9/522 (1.7%)
Millan-Rodriguez [15]
63/546 (11.5%) 63/1527 (4.1%)
Van der Meijden [16]
Local pathology
Review pathology
53/963 (5.5%)
67/953 (7.0%)
53/1767 (3.0%)
67/1278 (5.2%)
Witjes [17]
Local pathology
Review pathology
16/246 (6.5%)
13/254 (5.1%)
16/450 (3.6%)
13/450 (2.9%)
Total
Range
229/3299 (6.9%) 247/6093 (4.1%)
2.9% - 18.0%
1.7% - 9.3%
2. INCIDENCE
High grade papillary tumors that are confined to the
mucosa and do not invade the lamina propria are relatively rare. Based on 12 different series [5-17],
Table 1 shows that the incidence of high grade
tumors among Ta tumors varied from 2.9% to 18.0%,
with an average of 6.9% (229/3299 patients). The
incidence of high grade Ta tumors among all patients
with stage Ta or T1 tumors was 4.1% (247/6093
patients) and varied from 1.7% to 9.3%.
between 1973 WHO grades 2 and 3, so the figures
are not directly comparable. Also, this was a highly
selected group of patients with recurrent disease and
72% had concurrent carcinoma in situ (CIS).
Several papers have highlighted discrepancies
between local and review pathology in determining
both the tumor stage and grade. Witjes et al. found
that only 31% (5 /16) of patients initially classified
locally as having high grade Ta tumors were confirmed by review pathology while another 5 of 16
(31%) were reclassified as high grade T1 [17]. In
addition, 61.5% (8/13) of the tumors classified as
high grade Ta by the review pathologist were not
Conversely, Herr found that 125 of 148 patients with
Ta tumors (84.5%) had high grade tumors [18].
However, this study used the 1998 WHO/ISUP classification system, which does not distinguish
167
progression rates for patients with high grade Ta disease in 9 different series of patients with long-term
follow-up. It suggests that invasion of the lamina
propria occurs in as many as 40% of the patients, and
progression to muscle-invasive disease in about 20%
to 25% of the patients (Level 2).
classified as such by the local pathologist. In the
EORTC series [16], the agreement was even worse
(Table 2). Additional analyses showed that only 21%
(11/53) of tumors classified as high grade Ta by the
local pathologist were confirmed on pathology
review, and nearly 84% (56/67) of the patients classified as having high grade Ta tumors by the review
pathologist were not classified as such by the local
pathologist. Globally, only 23% of the patients classified as having high grade Ta tumors by the local
pathologist were confirmed by review pathology.
Thus, inaccuracies in staging and grading can result
in the misclassification of a substantial percentage of
patients with high grade Ta tumors (Level 3).
5. TREATMENT
Because high grade Ta tumors represent a relatively
small subgroup of patients and the histological diagnosis is subject to considerable misclassification,
there are no randomized trials comparing the efficacy of different treatment regimens in this patient subgroup. As they have a 20% to 25% chance of progression to muscle-invasive disease, patients with
high grade Ta bladder tumors should be treated and
followed as high-risk patients (Grade A, [23,24]).
3. DIAGNOSTIC WORK-UP
Due to the high rate of misclassification in patients
originally thought to have high grade Ta tumors, a
second-look TUR is indicated in order to reduce the
risk of understaging and residual disease (Level 3,
Grade B [19,20,21]). Bladder mapping biopsies to
determine the presence of CIS should be considered
due to the high incidence of concurrent CIS - 40% or
more - observed in several series (Level 3, Grade B,
[5,13,18]).
Thus, after TURBT, patients with tumors appearing
to be high grade Ta should receive 1 immediate instillation of chemotherapy (Grade A, [25]). They
should undergo a second-look TURBT and bladder
mapping biopsies 2 to 4 weeks later (Grade B). If
residual tumor is found, resect and give 1 immediate
instillation of chemotherapy. This is followed, 2 to 3
weeks later, once the diagnosis of high grade Ta has
been confirmed, by a 6-week induction course of
bacillus Calmette-Guérin (BCG) and 1 to 3 years of
maintenance BCG (Grade A, [26-28]). The optimal
maintenance schedule is unknown.
4. PROGNOSIS
Various publications have shown that although
tumor multiplicity is the most important prognostic
factor for recurrence, it is the grade that is the most
important prognostic factor for progression to muscle-invasive disease [15]. The difference in the progression rate between stages Ta and T1 appears to be
less important in high grade tumors [22]. How-ever,
across different series, assessment of the risk of progression in patients with high grade Ta tumors is difficult. This is not only due to inaccuracies in
staging and grading, but also due to small patient
numbers, differences in the grading system used, frequency of concomitant CIS, adjuvant treatment after
TURBT, rate of cystectomy, duration of follow-up,
and definition of progression (lamina propria or muscle invasion).
In case of failure before maintenance BCG has been
completed, consider cystectomy if high grade T1 or
CIS is present (Grade B). For other superficial recurrences, resect and continue maintenance BCG
(Grade B). If early failure occurs after maintenance
BCG has been completed, consider cystectomy
(Grade B). If later superficial recurrence occurs, consider restarting BCG or other instillations as an alternative to cystectomy (Grade B).
These patients require long-term follow-up (Grade
A), for example every 3 months during the first 2
years, every 4 months during the third year, every 6
months during the fourth and fifth years, and yearly
thereafter as long as there is no recurrence (Grade B,
[28]) (see decision tree at the end chapter).
Considering the above limitations, Table 3 presents
Table 2. High Grade Ta: Agreement Between Local and Review Pathology
Van der Meijden [16]
Witjes [17]
Total
Local High Grade Ta Confirmed by Review
11/53 (20.8%)
5/16 (31.3%)
16/69 (23.2%)
Review High Grade Ta Not Identified by Local
56/67 (83.6%)
8/13 (61.5%)
64/80 (80.0%)
168
Table 3. Progression of High Grade Ta Bladder Cancer
Reference
Treatment After TURBT
Progression
Death Due to Disease
Follow-up
Chen [6]
Chemotherapy
4/14 (28.5%) T1
3/14 (21.4%) T2
NA*
Mean 74 months
Heney [8]
None
1/4 (25.0%) T2
NA
Median 39 months
Herr [18]
ISUP
BCG
49/125 (39.2%) T1
32/125 (25.6%)
Min 15 years
Holmang [9]
None
Radiotherapy
Cystectomy
1/ 9 (11.1%) T2
NA
Min 20 years
Holmang [5]
None
Chemotherapy
Radiotherapy
6/13 (46.2%) T1b
NA
Min 5 years
None
3/16 (18.8%) T1
1/16 (6.3%) T2
1/16 (6.3%)
Median 106 months
Larsson [12]
None
Chemotherapy
Cystectomy
2/15 (13.3%) T1
1/15 (6.7%) T2
2/10 (20.0%)
Min 5 years
Lebret [13]
BCG
15/32 (46.9%) T1
8/32 (25.0%) T2
4/32 (12.5%)
Median 58 months
None
Chemotherapy
BCG
17/67 (25.4%) T2
NA
Max 14 years
Jakse [11]
Van der Meijden [16]
*NA: Data not available
Summary
II. CARCINOMA IN SITU
High grade Ta tumors defined according to the
1973 WHO grading classification system are relatively rare, accounting for approximately 7% of Ta
tumors and 4% of all Ta and T1 tumors. However,
inaccuracies in staging and grading can result in
the misclassification of 75% or more of patients
thought to have high grade Ta tumors.
A number of review papers on carcinoma in situ
(CIS) have been published [29-36], some of which
are based on previous bladder cancer consensus conferences. This review expands upon these previous
papers, taking into account recent publications.
However, the problem with many of these publications is that they are based on only a small number of
highly-selected patients and on retrospective analyses with different endpoints, evaluation criteria, and
durations of follow-up. It is thus difficult to obtain
evidence-based results.
A second look TUR and bladder mapping biopsies
are recommended. Since these patients have a
20% to 25% chance of progression to muscleinvasive disease, they should be treated and followed as high-risk patients. Thus, they should
receive 1 immediate instillation of chemotherapy
after TUR, a 6-week induction course of BCG,
and 1 to 3 years of maintenance BCG.
1. DEFINITION AND CHARACTERISTICS
CIS is a flat, high grade, noninvasive urothelial carcinoma (Figure 1). Using the 2002 TNM classifica-
169
2. INCIDENCE
It has been estimated that 5% to 10% of all patients
with superficial bladder cancer have CIS [33, 37,
38]. However, due to differences in patient selection,
the lack of a uniform definition and classification
system for CIS, and interobserver variability, especially between varying degrees of dysplasia and CIS,
the percent of patients with CIS varies from one
series to another. For example, Kaasinen found that
5% of patients with superficial bladder cancer had
concurrent CIS as compared to 19% reported by
Palou [38, 39].
Figure 1. CIS is a flat, high grade, noninvasive urothelial
carcinoma
3. DIAGNOSIS OF CIS
tion, CIS is classified together with Ta and T1 papillary tumors as a superficial bladder cancer [1].
Unlike low grade Ta and T1 tumors, CIS is a highly
malignant entity which, when left untreated, has a
much higher progression rate than most Ta and T1
tumors (Level 2, [29]). The term carcinoma in situ
might suggest that CIS is a precursor of cancer.
While it may be a precursor of invasive bladder cancer, the histological and cytological aspects of CIS
make this an overtly malignant entity in itself.
The diagnosis of CIS is made in most cases by a
combination of cystoscopy, urine cytology, and multiple bladder biopsies [31]. Of these, the histology of
bladder biopsies is determinant in establishing the
diagnosis. In CIS, the coherence and adherence of
epithelial cells is decreased and this feature often
results in denuded biopsies when taken by cold cup
or with the resection loop.
Standard (white-light) cystoscopy might reveal no
visible abnormalities at all, although multifocal red,
velvet-like patches are often visible (Figure 2). Zaak
et al. found that under white-light endoscopy 30% of
specimens with grade 2 dysplasia and 53% of specimens with CIS were missed [40].
Macroscopically, CIS can be missed at cystoscopy or
be considered as an inflammatory lesion if not biopsied. It is often multifocal and can occur in the upper
urinary tracts and in the prostatic ducts and urethra
[34].
In 1998, the WHO/ISUP consensus classification of
urothelial neoplasms of the urinary bladder defined
CIS as follows [3]:
The lesion is characterized by the presence of cells
with large, irregular, hyperchromatic nuclei that may
be either present in the entire thickness of the epithelium or only a part of it. Mitotic activity is frequently observed, often in the mid to upper urothelium.
CIS encompasses lesions which in the past were designated as severe dysplasia or marked atypia. By
definition, all CIS are high grade lesions. CIS should
not be subclassified by grade despite the spectrum of
pleomorphism seen within this entity.
Figure 2 CIS A multifocal red, velvet-like patches are often
visible
CIS is classified into 1 of 3 different clinical types
[33]:
Fluorescence cystoscopy, which is done with a porphyrin-based photosensitizer, (hex)-aminolevulinic
acid (HAL or ALA), will reveal areas in the bladder
that are suspicious for CIS and that cannot be seen
with white-light cystoscopy. In a group of 83 patients
with CIS, HAL cystoscopy detected CIS in 18
patients (22%) that was missed by traditional whitelight cystoscopy. [41] Although the use of fluores-
1. Primary CIS: isolated CIS with no previous or
concurrent papillary tumors
2. Secondary CIS: CIS detected during the follow-up
of patients with a previous papillary tumor
3. Concurrent CIS: CIS in the presence of papillary
tumors
170
and when biopsies from the bladder and prostatic
urethra are normal, CIS in the upper urinary tract
should be suspected, even though it is rare [47]. It is
possible to detect which renal unit is involved by
investigating the urine produced by each unit separately. Sampling is done using a ureteral catheter or
ureteroscopy. Brushing and biopsies of suspicious
areas are also possible, but in many cases neither
imaging nor biopsies will confirm the diagnosis. CIS
in the upper urinary tract may thus be diagnosed only
by repeated cytology.
cence cystoscopy improves the detection rate of CIS
to more than 95% (Level 2), it has not yet been
implemented on a regular basis in daily practice [41,
42].
Although CIS is defined as an overt high grade
lesion, consensus on the diagnosis does not always
exist when the specimen is reviewed by several
pathologists. There is both intraobserver and interobserver variability, even between severe dysplasia and
CIS. For example, Sharkey found a considerable discrepancy between local and review pathology: 15 of
69 (22%) cases of CIS were downgraded to dysplasia while 8 of 27 (30%) reports of dysplasia were
upgraded to CIS [43]. In addition, sampling errors
may also lead to an incorrect diagnosis.
4. PROGNOSIS
Patients with CIS fall into the high-risk group. Various publications have shown that the presence of CIS
is an adverse prognostic factor, especially for progression to muscle-invasive disease and death due to
bladder cancer. In a series of more than 1500
patients, CIS was the second most important
prognostic factor after grade (Level 2, [15]).
Both papillary tumors, and, especially, CIS, shed
cells in the urine. Due to a loss of cohesion of cells
in the epithelial lining of the bladder in CIS, there is
a larger number of floating cells in the urine as well
as a high degree of anaplasia. Classic urine cytology
will not detect low grade papillary tumors in all
cases. However, CIS is a disease that is nearly
always detected by urine cytology; both the sensitivity and specificity of urine cytology are over 90%.
Based on the natural history of CIS, approximately
54% of patients with CIS progress to muscle-invasive disease [29]. With BCG, a complete response
rate of about 70% to 80% can be achieved [33,4850]. However, even in complete responders, there is
still a high risk of extravesical recurrence (prostatic
urethra, ureters, renal pelves), progression within the
bladder, and death due to bladder cancer. Jakse found
a 5-year disease-free survival rate of 60% in 77 complete responders, 16 of whom (21%) died due to
bladder cancer [50]. In a group of 145 patients
treated with BCG, at 5 years Kaasinen found an
overall 54% disease-free rate, while 14% of patients
progressed to T1 or higher and 7% died due to bladder cancer (Level 2, [38]).
During the last decade, many new urine tumor
markers have become available such as NMP-22,
Immunocyt, BTA stat, and telomerase [44]. In a
comprehensive literature review and meta-analysis
in 348 patients with CIS, Lotan et al. have shown
that some urine-based bladder tumor markers may
have a sensitivity which is at least as good as cytology, but the specificity of these tests was not reported and the number of patients included in the various
studies was small [45]. Markers such as UroVysion,
HA-HAase, and BLCA-4 are promising as they all
have a high sensitivity to detect CIS [46]. However,
further studies are required before any of these markers can be recommended to replace classic urine
cytology (Level 2, Grade B).
5. PROGNOSTIC FACTORS
CIS
IN
PATIENTS
WITH
Controversy exists, however, whether cytology
should be derived from voided urine or from a bladder wash (barbotage). It has been stated that more
shedded cells are to be expected from rinsing the
bladder as compared to voided urine. However,
rinsing the bladder requires catheterization, which is
a minor but invasive procedure which sometimes
leads to urinary tract infection. On the other hand,
barbotage fluid can be examined in patients undergoing diagnostic or control cystoscopy.
Once CIS is diagnosed, there are no completely reliable prognostic factors that can be used to predict the
course of the disease, which can be quite variable.
The response rate in patients undergoing intravesical
treatment as well as the time point of re-sponse may
differ substantially from one patient to the next. It
would be of great help if prognostic
factors could be used to predict which patients will
ultimately respond to intravesical treatment and
which will not.
When high grade cells are found on cytology in the
absence of visible tumor on cystoscopy and IVU,
Lamm proposed a division of patients into 1 of 3
groups [29,33]:
171
1. asymptomatic unifocal primary CIS
the response will be durable. Even in complete
responders, lifelong monitoring of patients with CIS
is mandatory.
2. symptomatic multifocal (diffuse) primary CIS
3. CIS associated with prior or concurrent stage Ta
or T1 papillary tumors
Nevertheless, various publications have shown that
the response to intravesical treatment with BCG or
chemotherapy is an important prognostic factor for
subsequent progression and death due to disease.
Approximately 10% to 20% of complete responders
will eventually progress as compared to up to twothirds or more of nonresponders.
He hypothesized that the first group is the least
aggressive form of CIS, that the second group has a
poor prognosis with a high risk of extravesical extension, and that the third group was more heterogeneous.
Orozco defined 4 groups with an increasingly poor
prognosis [37]:
In a group of 111 patients with CIS and 80 patients
with high grade T1 urothelial carcinoma, the 3month response was the most important prognostic
factor for subsequent progression: 16 of 150 (11%)
complete responders progressed as compared to 27
of 41 (66%) nonresponders [55].
1. unifocal primary CIS
2. multifocal primary CIS
3. secondary CIS with noninvasive high grade
tumors
Hudson and Herr [30] reported that 7 of 105 (7%)
complete responders progressed at 5 years as compared to 25 of 75 (33%) incomplete responders. In a
small series, Van Gils-Gielen found that 6 of 34
(18%) complete responders progressed as compared
to 12 of 18 (67%) nonresponders [56]. Two of 34
(6%) responders died due to bladder cancer as compared to 5 of 18 (28%) nonresponders.
4. secondary CIS with high grade tumors that are or
become invasive
Hudson and Herr divided patients into 2 risk groups,
with good risk patients having unifocal CIS, a single
aneuploid line, cell surface receptors, tumor-associated or proliferative antigens, expression of normal
urothelial antigens, and a lack of p53 overexpression
[30].
Large differences in cystectomy rates between
responders and nonresponders have also been reported, approximately 10% in responders as compared to 50% in nonresponders [48,56].
These risk groups have never been properly validated, so no conclusions concerning their appropriateness can be drawn. Many prognostic factor publications are based on a retrospective analysis of small
patient series from a single institution. We will now
review various factors of potential prognostic importance (Level 3).
Treatment failure within the first 9 months after 6
weekly BCG instillations is also an alarming signal
that requires an immediate reassessment of the
patient to exclude muscle-invasive disease or extravesical CIS, either in the upper urinary tract or in the
prostatic urethra [57].
a) Age
Takashi, Cheng, and Griffiths all found that younger
patients (less than 60, 65, and 70 years, respectively)
had a better prognosis [51-53].
Thus, responders have a better prognosis than nonresponders, though early recurrence is also an ominous
sign.
b) Response to BCG
c) CIS versus Dysplasia
In complete responders, the median duration of
response is approximately 5 to 6 years [50,54]. In 77
complete responders not receiving maintenance
BCG, after a median follow-up of 7.6 years, 39%
recurred in the bladder, 17% had a locoregional
extravesical recurrence, 9% developed distant metastases, and 21% died due to bladder cancer [50]. In
another series of 55 complete responders receiving
maintenance BCG, after a median follow-up of 5.6
years, 33% recurred in the bladder and 11% died due
to bladder cancer [54]. Thus, a complete response of
CIS after intravesical treatment does not mean that
Assessment of the prognostic importance of CIS relative to dysplasia is difficult since the distinction
between CIS and dysplasia is variable from one
observer to the next. As mentioned, Sharkey found a
considerable discrepancy between local and review
pathology [43]. Given this variability and the small
number of patients included in many series, contradictions exist in the literature concerning the
prognostic importance of dysplasia relative to CIS.
In the 2 largest series, Millan-Rodriguez found CIS
but not dysplasia to be of prognostic importance
172
unifocal or multifocal, is defined differently by different authors. Multifocality has been variably
defined as the presence of CIS in at least 2, at least 3,
or at least 4 different sites.
[15]; however, Kiemeney found that patients with
CIS or dysplasia in random biopsies had a higher risk
of an increase in tumor stage at 3 years as compared
to patients with normal mucosal biopsies, with the
difference being the largest for patients with CIS
[58].
Some 50% to 70% of patients have at least 2 sites
involved [15,49,52,54,65,66], 25% to 45% at least 3
sites [52,56], and about 20% at least 4 sites [50].
Cheng found that urothelial dysplasia is a significant
risk factor for the development of CIS and invasive
carcinoma [59]. In 36 patients with primary untreated urothelial dysplasia, 7 patients (19%) progressed: 4 developed CIS and 3 developed invasive
disease.
Riddle found that 1 of 13 (8%) patients with unifocal
disease (one site) progressed compared to 18 of 23
(78%) patients with at least 2 sites involved [65].
Other authors could not show the prognostic importance of the extent of the disease, but the number of
patients studied was often small and therefore inadequate [49,51,52,56].
d) Type of CIS
The frequency of primary CIS relative to secondary
and concurrent CIS varies among different publications, ranging from 9% to 69% [60,61]. In 3 recent
studies with more than 100 patients each, 17% to
23% of patients with CIS were primary [50,53,54].
In another large series of 304 patients with CIS [38],
30% were primary, 42% secondary, and 28% concurrent. Twenty-eight percent were primary in a
retro-spective register of 102 patients with CIS [37].
The risk of secondary CIS increases according to
papil-lary tumor grade and stage [62].
f) Irritative Bladder Symptoms
As many as 25% of patients with CIS are asymptomatic at diagnosis [33]. The percent of patients
with irritative bladder symptoms varies between
40% and 75% in different series [51,52,67,68].
Norming found that there was progression (to T1 or
higher) in 29 of 45 (64%) patients with irritative
bladder symptoms compared to 8 of 18 (44%)
patients without irritative bladder symptoms [68].
Neither Cheng nor Takashi could show the prognostic importance of irritative bladder symptoms
[51,52].
There is no difference in the complete response rate
to BCG according to type of CIS [50,51,53]. Kaasinen reported that patients with concurrent CIS had
the highest progression rate (T1 or higher) and those
with primary CIS the lowest [38]. Ovesen found
that 1 of 13 (8%) patients with primary CIS progressed as opposed to 26 of 47 (57%) patients with
secondary or concurrent CIS [63]. Orozco observed
that 8 of 29 (28%) patients with primary CIS
increased in stage as compared to 43 of 73 (59%)
patients with secondary or concurrent CIS [37]. Two
of 29 (7%) patients with primary CIS died of bladder
cancer as opposed to 33 of 73 (45%) patients with
secondary or concurrent CIS. Losa found a higher
risk of progression in CIS associated with T1 papillary tumors as compared to CIS alone on BCG [49].
Likewise, Griffiths also found a higher progression
and death rate in patients with concurrent T1 tumors
[53].
g) Hematuria
Most patients have at least microscopic hematuria
[33] and 40% to 50% have macroscopic hematuria
[51,52]. Takashi found that the patients (43/84, 51%)
with gross hematuria had a significantly lower complete response rate, 63% versus 85% [51]. Cheng
could not show the prognostic importance of macroscopic hematuria, which was present in 54 of 138
(41%) patients, for either progression-free or cancerspecific survival [52].
h) Molecular Markers
Despite some authors having found that DNA ploidy
[68] and the loss of E-cadherin expression [69] predict stage progression in CIS patients, the use of
molecular markers and cell cycle regulators has not
provided a tool that can be used in daily practice to
predict their response and prognosis [69].
Thus, overall, patients with primary CIS have the
best long-term prognosis while those with concurrent CIS have the worst.
Anomalies of the p53 tumor suppressor gene have
been the most thoroughly investigated. Data suggest
that p53 overexpression after BCG treatment may be
more important than p53 overexpression prior to the
start of treatment. In a small group of 23 patients
with CIS, Ick reported that p53 overexpression was
present in 21 (90%) patients as compared to 0 of 11
e) Extent of CIS
Multifocal (diffuse) CIS is typically associated with
irritative symptoms and may extend to the distal
ureter and/or prostatic urethra in up to 30% to 50%
of cases [64]. However, the extent of CIS, whether
173
with intravesical chemotherapy or BCG, 67%
recurred, 12.5% in the bladder and 54.5% in extravesical locations. In 23 nonresponders, 51% develped
extravesical disease [60]. Patients with extra-vesical
involvement had worse disease-free and cancer-specific survival as compared to CIS patients without
extravesical involvement, especially when there was
panurothelial disease. In another series, Herr reported upper urinary tract recurrence in 19 of 66 (29%)
patients with CIS after a complete response in the
bladder with BCG [74]. Intravesical treatment does
not affect the prostatic urethra or the upper urinary
tract, areas that the instillations do not reach (Level
3). Due to the panurothelial nature of CIS, close
monitoring of the upper urinary tract and prostate is
required.
patients with dysplasia. [70] Ick also found that residual CIS with persistent p53 overexpression after
BCG treatment was linked to a high rate of progression [70]. Likewise, Ovesen reported that posttreatment p53 overexpression was related to progression
(9 of 10 (90%) p53-positive patients progressed as
compared to 18 of 49 (37%) p53-negative patients)
[63]. Among patients with a complete response, 7 of
34 (21%) patients who were p53-negative after treatment progressed as compared to 3 of 3 (100%) who
were p53-positive.
In a group of 33 patients, Sarkis found that pretreatment p53 was related to both stage progression (3 of
18 (17%) progressed to T1 or higher in p53-negative
patients compared to 13 of 15 (87%) in p53-positive
patients) and death due to bladder cancer [71].
Shariat observed that pretreatment p21 overexpression was related to an increase in stage while patients
who were both p21- and p53-positive had the highest
risk of stage increase [72].
6. TREATMENT OF CIS
If concurrent CIS is found in association with a muscle-invasive bladder cancer, the therapy for the
patient is determined according to the invasive
tumor. If concurrent CIS is found in association with
a noninvasive tumor (Ta or T1), TUR of the papillary tumors is mandatory for correct staging. No consensus exists thereafter whether conservative (intravesical instillations) or aggressive therapy (cystectomy) should be done, especially when there are concurrent high grade papillary tumors. Randomized trials between instillation therapy and early cystectomy
as immediate primary treatment are lacking [36].
Tumor-specific survival rates of early cystectomy
series in CIS are excellent, but as many as 40% to
50% of patients may be overtreated. Radiotherapy is
not a viable treatment option for CIS.
Assessment of the prognostic importance of p53
across different studies is difficult due to differences
in study design, patient selection, choice of the antibody, use of different cutoff values, and small patient
numbers [73]. In a review of 138 p53 publications,
comprising 3764 patients in 43 trials, no conclusions
could be drawn by the authors due to methodological
differences in technical aspects, selection of laboratory kits, and especially variations in the cutoff values used to classify a test as being positive or negative [73].
No definitive conclusions on the value of tumor
markers can be drawn due to the quality of the available data. Thus, the use of tumor markers to predict
response to treatment is not recommended in daily
practice (Grade B).
In his review of 497 patients, Lamm reported that
intravesical chemotherapy produced a complete response rate of 48%: 38% in 89 patients treated with
thiotepa, 48% in 212 patients treated with doxorubicin, and 53% in 196 patients treated with mitomycin C (MMC) [33]. There was, however, considerable variability with the same drug from one study
to the next. In 1496 patients treated with BCG, the
com-plete response rate was 72% (Level 2). In 2
recent studies of BCG, complete response rates of
83% and 93% were achieved [49,50].
i) Extravesical Extension
Patients with CIS are at a high risk of extravesical
involvement. Solsona found that 27 of 138 (19.5%)
patients with CIS had extravesical involvement at
baseline, 6 (4.3%) in the upper tract and 21 (15.2%)
in the prostate [47,60]. A total of 34 of 138 (24.6%)
patients with CIS had or developed upper urinary
tract tumors as compared to 18 of 786 (2.3%)
patients with only superficial papillary tumors.
When there was upper tract involvement, 23 of 34
(68%) also had prostate involvement (panurothelial
disease). Overall, 87 of 138 (63%) patients with CIS
developed extravesical involvement.
The classic induction course of BCG consists of 6
consecutive weekly intravesical instillations. Some
40% to 60% of patients not responding after this initial induction course respond to a second cycle of 6
weekly instillations (Level 2, [49,50,54,57,61,75]).
There are 2 important limitations to drawing conclu-
In 88 patients with CIS who had a complete response
174
sions based on an overview of complete re-sponse
rates in different studies:
MMC had a complete response compared to 21 of
36 (58%) patients on electromotive MMC. Based
on a median follow-up of 43 months, 9 of 36
(25%) patients on passive MMC were disease-free
as compared to 17 of 36 (47%) patients on electromotive MMC.
1. There may be important differences between studies with respect to the definition of CIS, patient
characteristics, and assessment of response to
treatment.
MMC plus BCG was compared to BCG alone in 2
studies. No results are available in 33 patients with
CIS randomized in CUETO trial 93008 [86]. In the
only large-scale study, the Nordic trial compared
alternating MMC and BCG instillations to BCG
alone in 304 patients with CIS [38]. No difference in
the complete response rate was seen between the 2
treatment groups: 119 of 159 (75%) patients on the
combination had a complete response compared to
120 of 145 (83%) patients on BCG alone. However,
based on a median follow-up of 56 months, there
was a significantly longer disease-free interval in the
BCG monotherapy arm: 80 of 145 (55%) patients
were disease-free on BCG alone compared to 72 of
159 (45%) patients on the combination of BCG and
MMC.
2. An initial complete response is not always durable.
As approximately 50% of complete responders
may eventually recur with risk of invasion or
extravesical recurrence [31,50,75,76], one must
take into account the long-term disease-free and
progression-free rates.
Treatment recommendations should only be based
on the results of randomized clinical trials with longterm follow-up. Unlike papillary tumors, few randomized trials on the treatment of CIS have been
published. In addition, there are relatively few randomized trials in patients with CIS alone. Most trials
include patients with either papillary tumors or CIS,
resulting in only a small number of patients with CIS
being entered. Thus, the power to detect treatment
differences is low and the reliability of the conclusions is limited.
Eleven randomized trials comparing different
chemotherapy regimens were identified; however, 6
of the studies included less than 25 patients with CIS
so no conclusions can be drawn from them:
An alternating schedule of MMC and BCG is not
superior to BCG alone (Level 1). Due to insufficient
data, no other conclusions can be drawn from randomized studies concerning the relative effectiveness of the different chemotherapeutic agents. Electromotive MMC requires further study to assess its
merit. Nonrandomized trials suggest that thiotepa
may be inferior to adriamycin and MMC (Level 3).
1. Standardized versus optimized MMC [77]
b) Randomized Interferon Alpha 2b Trials
2. MMC plus adriamycin maintenance versus no
maintenance after complete response on the combination [78]
High dose intravesical interferon (100 million units)
produced a significantly higher complete response
rate than low dose interferon (10 million units): 20 of
47 (43%) versus 2 of 38 (5%). At 12 months, the disease-free rates were 21% and 3%, respectively [67].
Intravesical interferon alpha 2b is thus active in the
treatment of CIS (Level 1).
a) Randomized Trials Comparing Different
Chemotherapy Regimens
3. Thiotepa versus MMC [79]
4. Adriamycin versus thiotepa [80]
5. Adriamycin versus MMC [81]
c) Randomized Trials Comparing BCG to
Chemotherapy
6. BCG plus epirubicin versus BCG alone [82]
A second study compared adriamycin to MMC in 40
patients with CIS, though separate results were not
given by treatment group [83].
For more than 20 years, intravesical BCG, a nonspecific immunotherapy, and intravesical chemotherapy,
with drugs such as thiotepa, adriamycin, epirubicin,
and mitomycin C, have been used in the treatment of
CIS. The relevant clinical question is whether intravesical BCG is more effective than intravesical
chemotherapy in the treatment of CIS.
Two other underpowered trials with MMC
compared:
1. MMC to thiotepa [84]: 7 of 29 (24%) patients
with CIS on thiotepa had a complete response
compared to 8 of 24 (33%) on MMC
Twelve randomized trials including 845 patients with
CIS compared BCG to different chemotherapy regimens:
2. Passive to electromotive MMC [85]: At 6 months,
11 of 36 (31%) patients with CIS on passive
175
1. BCG VERSUS MMC (5 TRIALS)
4. BCG VERSUS EPIRUBICIN (1 TRIAL)
In a Swedish-Norwegian study [87], 83 patients with
CIS or dysplasia were randomized to BCG or MMC.
With a median follow-up of 64 months, 23 of 41
(56%) patients on BCG remained disease-free as
compared to 14 of 42 (33%) on MMC. In just the
patients with CIS, the 5-year recurrence-free rates
were 55% and 26%, respectively.
De Reijke found that 55 of 84 (65%) patients on
BCG had a complete response as compared to 47 of
84 (56%) on epirubicin [54]. The duration of complete response was longer on BCG: 18 of 55 (33%)
complete responders on BCG recurred as compared
to 31 of 47 (66%) on epirubicin.
5. BCG
TRIAL)
A SWOG study reported a complete response rate of
17 of 31 (55%) on BCG and 16 of 35 (46%) on
MMC [88].
7. BCG AND MMC VERSUS MMC ALONE (2 TRIALS)
In Finnbladder 2 [66], at 6 months 21 of 28 (75%)
patients on MMC and BCG had a complete response
compared to 20 of 40 (50%) on MMC alone. Based
on a mean follow-up of 33 months, 20 of 28 (71%)
patients on MMC and BCG were disease-free compared to 17 of 40 (43%) on MMC alone.
A sixth trial, Finnbladder 1 [91], which included only
18 patients with CIS, was not properly randomized
and thus is not included in this assessment.
In a Dutch study [95], separate results are not av-ailable for the 65 patients with CIS, 29 of whom were
randomized to MMC and BCG and 36 to MMC
alone.
2. BCG VERSUS ADRIAMYCIN (1 TRIAL)
Lamm reported a significantly higher complete response rate and longer disease-free interval in complete responders on BCG as compared to adriamycin: 45 of 64 (70%) had a complete response
versus 23 of 67 (34%); based on a median follow-up
of 65 months, 26 of 45 (58%) complete responders
on BCG remained disease-free as compared to 8 of
23 (35%) on adriamycin [92]. The estimated 5-year
disease-free survival rates were 45% and 18%, respectively.
VERSUS
TUR ALONE (1
In this study [94], 18 of 21 (86%) patients on BCG
had a complete response compared to 17 of 21 (81%)
on sequential MMC and adriamycin. However, 27 of
42 (64%) patients did not have CIS but rather dysplasia (reported as “grade 2” CIS). Based on a mean
follow-up of 47 months, 6 of 21 (29%) on
chemotherapy remained disease-free as compared to
16 of 21 (76%) on BCG.
In an Italian study comparing BCG to MMC [85], 23
of 36 (64%) on BCG and 11 of 36 (31%) on MMC
had a complete response at 6 months. However, in a
third arm with electromotive MMC, 21 of 36 (58%)
had a complete response. Based on a median followup of 43 months, 17 of 36 (47%) on BCG, 9 of 36
(25%) on passive MMC, and 17 of 36 (47%) on electromotive MMC remained disease-free.
ADRIAMYCIN
VERSUS
6. BCG VERSUS MMC AND ADRIAMYCIN (1 TRIAL)
A Dutch study compared 2 different strains of BCG,
Tice and RIVM, to MMC: 26 of 38 (68%) on BCG
and 8 of 12 (67%) on MMC had a complete response
[90].
VERSUS
EPIRUBICIN
Only 9 patients with CIS were entered in this study
[93].
Based on a median follow-up of 7.2 years, the
EORTC/Dutch study found that 11 of 22 (50%) on
BCG remained disease-free as compared to 7 of 16
(44%) on MMC [89].
3. BCG
TRIAL)
VERSUS
8. SUMMARY
The results of the trials comparing BCG to
chemotherapy are summarized in Tables 4 and 5,
both by type of chemotherapy and overall. In over
600 patients, there was a 68% complete response rate
on BCG and a 49% complete response rate on
chemotherapy (Table 4). In the complete responders,
68% of patients treated with BCG remained diseasefree as compared to 47% of patients receiving
chemo- therapy, based on a median follow-up of 3.75
years. The overall disease-free rates were 51% and
27%, respectively (Table 5).
THIOTEPA (1
Only 17 patients with CIS were randomized to the 3
treatment groups [80]. No conclusions can be drawn
due to the small number of patients entered.
As compared to chemotherapy, treatment with BCG
thus increased both the complete response rate and
the overall percent of patients remaining disease-free
176
Table 4. BCG versus Chemotherapy: Complete Response Rate in Patients With CIS
Reference
BCG
Chemotherapy
BCG versus MMC
Di Stasi [85]
Vegt [90]
Witjes [89]
Lamm [88]
Malmstrom [87]
Total
23/36
26/38
NA*/24
17/31
NA/41
66/105 (63%)
11/36
8/12
NA/16
16/35
NA/42
35/83 (42%)
BCG versus electro MMC
Di Stasi [85]
23/36 (64%)
21/36 (58%)
BCG versus Adriamycin
Lamm [92]
Martinez-Pineiro [80]
Total
45/64
NA/6
45/64 (70%)
23/67
NA/6
23/67 (34%)
BCG versus Epirubicin
De Reijke [54]
Melekos [93]
Total
55/84
NA/4
55/84 (65%)
47/84
NA/3
47/84 (56%)
NA/6
NA/5
BCG versus MMC + ADM
Sekine [94]
18/21 (86%)
17/21 (81%)
BCG + MMC versus MMC
Witjes [95]
Rintala [66]
Total
NA/29
21/28
21/28 (75%)
NA/36
20/40
20/40 (50%)
205/302 (68%)
163/331 (49%)
BCG versus Thiotepa
Martinez-Pineiro [80]
Overall Total
* - NA: Data not available
(84%) during maintenance, showing the benefit of
additional treatment in the initial BCG nonresponders (Level 1). CIS complete responders apparently had a longer recurrence-free survival with
maintenance.
(Level 1). Treatment with electromotive MMC
requires further study before any conclusions can be
drawn concerning its long-term efficacy.
d) Randomized Trials Comparing BCG to TURBT
Alone
Seventy-two of 93 patients in the Badalament study
had concurrent CIS. Overall, there was no difference
in treatment efficacy between 2 years of maintenance BCG and no maintenance [97]. However, separate results were not provided for just the patients
with CIS.
Based on a minimum follow-up of 3 years, 15 of 23
(65%) patients were disease-free on BCG compared
to 0 of 26 patients who had TURBT alone [96]. Thus
only TURBT or the coagulation of CIS lesions is not
by itself sufficient treatment (Level 1).
e) Randomized Trials Comparing BCG
Maintenance to No Maintenance
Only 11 patients with CIS were randomized in the
Hudson trial [98], so no conclusions can be drawn.
In the SWOG trial [75], 233 patients with CIS were
randomized at 3 months to no maintenance or to 3
years of maintenance. The complete response rate in
the maintenance arm improved from 64 of 117
(55%) at the time of randomization to 97 of 117
f) Randomized Trials Comparing BCG to
Bropirimine
Twenty-three of 28 (82%) patients on BCG had a
complete response compared to 22 of 27 (81%) on
177
Table 5. BCG versus Chemotherapy: Disease-free Rate in Patients With CIS
Reference
BCG
Chemotherapy
Median
Follow-up (yrs)
BCG versus MMC
Di Stasi [85]
Vegt [90]
Witjes [89]
Lamm [88]
Malmstrom [87]
Total
17/36
NA*/38
11/22
NA/31
23/41
51/99 (52%)
9/36
NA/12
7/16
NA/35
14/42
30/94 (32%)
3.6
3.0
7.2
2.5
5.3
BCG versus Electromotive MMC
Di Stasi [85]
17/36 (47%)
17/36 (47%)
3.6
BCG versus Adriamycin
Lamm [92]
Martinez-Pineiro [80]
Total
26/64
4/6
30/70 (43%)
8/67
0/6
8/73 (11%)
5.4
3.0
BCG versus Epirubicin
De Reijke [54]
Melekos [93]
Total
37/84
NA/4
37/84 (44%)
16/84
NA/3
16/84 (19%)
5.6
4/6 (67%)
3/5 (60%)
3.0
BCG versus MMC + ADM
Sekine [94]
16/21 (76%)
6/21 (29%)
3.9
BCG + MMC versus MMC
Witjes [95]
Rintala [66]
Total
NA/29
20/28
20/28 (71%)
NA/36
17/40
17/40 (43%)
2.8
154/302 (51%)
97/353 (27%)
3.75
BCG versus Thiotepa
Martinez-Pineiro [80]
Overall Total
*- NA: Data not available
bropirimine [99]. Based on a maximum follow-up of
3 years, 20 of 23 (87%) complete responders on
BCG remained disease-free compared to 14 of 22
(64%) complete responders on bropirimine.
among patients with CIS, there was a significantly
lower disease-free survival rate on the standard dose,
150 mg: 33% versus 62% at 5 years.
h) BCG Meta-analysis of Progression
g) Randomized Trials Comparing Full-dose to
Reduced-dose BCG
In 403 patients with CIS, BCG reduced the risk of
progression by 35% as compared to either intravesical chemotherapy or a different immunotherapy (OR
= 0.65, 95% CI 0.36 to 1.16, P = 0.10). Twenty-five
of 212 (12%) patients on BCG progressed as compared to 31 of 191 (16%) patients receiving these
other treatments (Level 1, [26]).
Two trials including patients with CIS have compared different doses of BCG with apparently conflicting results:
1. Thirty-nine patients with CIS were randomized to
27 or 81 mg of Connaught BCG [100]. There was a
trend to higher progression and death rates in the
reduced-dose arm.
i) Treatment of Extravesical CIS
The treatment of CIS in the upper urinary tract consists of rinsing the renal unit with BCG or with
chemotherapeutic drugs such as mitomycin C or
epirubicin. The watery solutions can be introduced
2. In another study, the number of patients with CIS
who were randomized to 75 versus 150 mg of
Pasteur BCG was not reported [101]. However,
178
into the upper urinary tract using a ureteral stent or
nephrostomy catheter [74,102].
stopped BCG due to side effects did so during the
first 6 months of treatment (Level 1, [106]).
Only anecdotal cases have been reported and experience is therefore limited. Thalmann found that 19 of
22 (86%) patients (25 renal units) with upper urinary
tract CIS responded to BCG perfusions [103]. Nine
patients (41%) died of their disease after a median
follow-up of 50 months (Level 3).
While BCG-associated cystitis is more frequent than
that with mitomycin C, Bohle concluded that it did
not differ according to whether BCG maintenance
treatment was given or not [27]. Saint and Morgia
also concluded that the side effects of BCG were the
most prominent during the induction and early maintenance instillations [107,108].
Response to the treatment is determined by conversion of cytology in urine derived from the upper urinary tract from high grade to negative. If no response is achieved, a nephroureterectomy should be
considered. Before performing a radical cystectomy,
the urologist should know whether the prostatic urethra is free of CIS. During cystectomy, the distal
ureters should also be investigated for the presence
of CIS [31].
Thus, the assumption that BCG-induced side effects
increase with time during maintenance does not
appear to be correct (Level 1).
k) Treatment of BCG Failures
For BCG-refractory CIS, Kim [35] presented a
review of the role of both radical cystectomy and
conservative therapy with valrubicin [109-111],
interferon alpha 2b [67,112,113], BCG plus interferon alpha 2b [114], bropirimine [115-118], and
photodynamic therapy [119-122].
If CIS is found in the prostatic urethra, this is an ominous sign [31]. Three different entities might be
encountered. CIS may be present only in the epithelial lining of the prostatic urethra. However, CIS
might also grow in the prostatic tissue following the
prostatic ducts. In the worst case scenario, CIS may
be found in the prostatic tissue stroma (T4) and this
has the worst prognosis of all. Cystoprostatectomy is
advised when CIS is found in the stroma. In the other
2 situations, a TUR of the prostate can be performed
followed by intravesical instillations of BCG [31].
Radical cystectomy is the treatment that is offered to
most patients when intravesical treatment has failed
[28]. The timing of cystectomy remains a challenge
and is still controversial. About 70% of patients
treated with an initial BCG induction course of 6
weeks will respond, thus a considerable number of
patients will require additional BCG instillations
before biopsies and cytology become negative.
Approximately 40% to 60% of patients not responding after an initial course of 6 weekly instillations
will respond to a second cycle of 6 weekly instillations (Level 2, [49,50,54,57,61,75]). Additional complete responses have also been encountered if, after
the initial induction course of 6 weeks, maintenance
cycles consisting of 3 weekly booster instillations are
given (Level 1, [75]). On the other hand, the likelihood of progression to muscle-invasive disease or
the development of metastases increases with the
number of unsuccessful courses. Thus, doubt
remains concerning the best time point to abandon
conservative treatment and proceed to cystectomy.
For further details concerning the treatment of CIS
involving the ureters and prostatic urethra, see Kurth
and Lamm [31,33].
j) BCG Toxicity
Because of the more pronounced side effects of BCG
as compared to intravesical chemotherapy [54,80,
85,88,90,92], reluctance still exists about its use.
However, with increasing experience in applying
BCG, serious side effects are now encountered in
less than 5% of patients and can be effectively treated in virtually all cases [104].
In a large randomized SWOG study [75], only 16%
of patients completed the entire 3-year maintenance
schedule, suggesting that maintenance BCG is too
toxic (Level 1). In a recent EORTC trial including
487 patients treated with BCG [105,106], about onethird of the patients completed the 3 years of maintenance and 99 (20%) stopped due to adverse events.
Local BCG side effects did not increase during maintenance and systemic side effects were more frequent
during the first 6 months of treatment, after which
time they decreased. Two-thirds of all patients who
In patients for whom cystectomy is not possible,
conservative treatment may be considered [123]. In
the largest series of BCG-refractory patients with
CIS, complete response rates of 19 of 90 (21%) on
valrubicin [109], 10 of 22 (45%) on interferon alpha
2b [113], 21 of 65 (32%) on bropirimine [115], and
21 of 36 (58%) and 13 of 27 (48%) on photodynamic therapy [120,121] were observed. In a large phase
II study of BCG plus interferon alpha 2b, separate
results were not presented for the patients with CIS
179
who had previously failed BCG [114]. A phase I
study of intravesical gemcitabine included 18 BCGrefractory patients, 14 of whom had CIS. Seven of
the 18 (39%) patients had a complete response [124].
In summary, BCG plus interferon alpha 2b, photodynamic therapy, and gemcitabine all warrant further
evaluation in order to determine their role in the
treatment of BCG-refractory patients (Level 3).
Summary
CIS is a flat, high grade carcinoma occurring in
5% to 10% of patients with superficial bladder
cancer. Diagnosis is made by a combination of
cystoscopy, cytology, and multiple bladder biopsies with histology being the determining factor.
The marker of choice is cytology. Patients with
CIS are at high risk of progression; however, there
are no prognostic factors that accurately predict
the course of the disease. Immediate cystectomy
may be overtreatment in up to 50% of the patients.
Evidence-based results of intravesical treatment
are limited by the small number of patients treated in randomized trials. A 6 week induction
course of BCG and 1 to 3 years of maintenance
BCG are recommended since intravesical BCG
increases both the complete response rate and
long-term disease-free rate as compared to intravesical chemotherapy.
180
RECOMMENDATIONS
I. TREATMENT AND FOLLOW-UP OF HIGH
GRADE Ta UROTHELIAL CARCINOMA
pathologist in separate, properly labeled containers,
for example one container with the exophytic part of
the tumor, one with the underlying muscle, another
with the random mucosal biopsies, and another with
biopsies from the prostatic urethra [125].
3. The marker of choice for the detection and follow-up
of patients with CIS is cytology (Grade B). It is recommended to perform cytology with voided urine
unless a bladder wash is done at the time of cystoscopy (Grade B).
b) Detection, Treatment, and Follow-up of CIS
1. The best marker to diagnose CIS or to assess response to treatment is cytology. None of the other
currently available markers have been proven to be
superior (Grade B).
2. Radical cystectomy at the time of diagnosis of CIS,
instead of instillation therapy, provides excellent disease-free survival but is overtreatment in up to 50%
of the patients (Grade A).
3. The treatment of CIS with intravesical BCG is recommended since it provides the highest rate of complete response as well as the highest long-term disease-free rate among intravesical treatments (Grade
A).
4. Six weeks only of BCG is suboptimal treatment for
CIS. Maintenance BCG treatment is required but the
optimal maintenance schedule is un-known. In the
absence of treatment failure, at least one year of
maintenance BCG is recommended (Grade A).
5. The response to intravesical BCG should be assessed 3 months after starting treatment. If no response is seen, one might offer the patient either cystectomy, another 6-week course of BCG, or to continue with 3 weekly boosters (Grade B). As approximately 50% of patients will respond to a second
course of BCG, cystectomy at 3 months is overtreatment in about 50% of the patients. While failure at
3 months is a poor prognostic factor, the optimal
time to abandon conservative treatment and proceed
to cystectomy is unknown. Note: response of CIS in
the bladder does not influence the course of CIS outside the bladder (upper urinary tract and prostatic
urethra).
6. If a complete response has not been achieved at 6
months, the therapy of choice is radical cystectomy
(Grade B). In patients for whom a cystectomy is not
possible, one of the conservative treatments mentioned above may be considered (Grade B).
7. Patients with CIS, even complete responders, should
be monitored lifelong due to the high risk of recurrence and progression, both within the bladder and
extravesically (Grade A).
1. As they have a 20% to 25% chance of progression to
muscle-invasive disease, patients with high grade Ta
bladder tumors should be treated and followed as
high-risk patients (Grade A, [23,24]).
2. After TURBT, it is thus recommended that patients
with tumors appearing to be high grade Ta receive
one immediate instillation of chemotherapy (Grade
A, [25]).
3. These patients should undergo a second-look
TURBT and bladder mapping biopsies 2 to 4 weeks
later (Grade B). If residual tumor is found, resect
and give 1 immediate instillation of chemotherapy.
4. This is followed, 2 to 3 weeks later, once the diagnosis of high grade Ta has been confirmed, by a 6-week
induction course of bacillus Calmette-Guérin (BCG)
and 1 to 3 years of maintenance BCG (Grade A, [2628]). The optimal maintenance schedule is unknown.
5. In case of failure before maintenance BCG has been
completed, consider cystectomy if high grade T1 or
CIS is present (Grade B). For other superficial recurrences, resect and continue maintenance BCG
(Grade B).
6. If early failure occurs after maintenance BCG has
been completed, consider cystectomy (Grade B). If
later superficial recurrence occurs, consider re-starting BCG or other instillations as an alternative to
cystectomy (Grade B).
7. These patients require long-term follow-up (Grade
A), for example every 3 months during the first 2
years, every 4 months during the third year, every 6
months during the fourth and fifth years, and yearly
thereafter as long as there is no recurrence (Grade
B, [28]).
II. CARCINOMA IN SITU OF THE
BLADDER
a) Diagnosis of CIS
1. Flourescence cystoscopy should be considered
because it has a greater sensitivity than white light
cystoscopy (Grade B).
2. All suspicious areas in the bladder should be biopsied. In patients with concurrent high grade Ta and in
all T1 papillary tumors, a second-look TUR should
be done (Grade B). In patients with a positive cytology, random biopsies including the prostatic urethra
should be taken (Grade B). A bladder diagram
should be used to identify the exact location where
biopsies have been taken. For a proper pathological
assessment of the extent of the disease, it is recommended to submit different types of material to the
181
Algorithm 1. Treatment Recommendations for High Grade Ta Urothelial Carcinoma
TURBT of tumor suspicious for high grade Ta
One immediate (postoperative) instillation of
chemotherapy (Grade A)
Second-look TURBT 2 to 4 weeks later (Grade B)
Bladder mapping biopsies for CIS (Grade B)
Residual tumor: Resect;
One immediate instillation of chemotherapy
(Grade A)
No residual tumor.
Confirmed high grade Ta
2 to 3 weeks later: 6-week induction
course of BCG followed by 1 to 3 years
maintenance BCG (Grade A)
Long-term follow-up (Grade A)
Schedule (Grade B): every 3 months first 2 years,
every 4 months 3rd year, every 6 months
4th and 5th years, then yearly
Failure before BCG maintenance
complete
If high grade
T1 or CIS
Recommend
cystectomy
(Grade B)
Superficial
recurrence
Resect, continue
maintenance BCG
(Grade B)
Failure after BCG
maintenance complete
Early failure
Consider cystectomy
(Grade B)
182
Late superficial
recurrence
• consider
restarting BCG or other
instillations or Perform a
cystectomy (Grade B)
Algorithm 2. Treatment Recommendations for CIS
Diagnosis of CIS
Intravesical BCG, 6 weeks (Grade A)
Assess response at 3 months
COMPLETE RESPONSE
NO COMPLETE RESPONSE
Radical cystectomy
OR
Another 6-week course of
BCG or 3 weekly BCG
boosters (Grade B).
Assess response at
6 months
COMPLETE
NO COMPLETE RESPONSE
RESPONSE
Cystectomy standard
(Grade B)
OR
Maintenance BCG for at least
1 year (Grade A)
If cystectomy not possible,
conservative treatment
(Grade B)
Lifelong monitoring with
cystoscopy and cytology
(Grade A)
183
grade assessment of stages Ta and T1 bladder tumors: a combined analysis of 5 EORTC cancer trials. J Urol 164, 1533 1537, 2000.
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187
188
Committee 5
T1 Urothelial Carcinoma of the Bladder
Chair
M.A.S. JEWETT (CANADA)
Members
A.M. NIEDER (USA)
M. BRAUSI (ITALY)
D. LAMM (USA)
M. O’DONNELL (USA)
K. TOMITA (JAPAN)
H. WOO (AUSTRALIA)
189
CONTENTS
I. DIAGNOSIS AND STAGING
II. TREATMENT
1. TECHNIQUE OF RESECTION
1. ROLE OF IMMEDIATE ADJUVANT
INTRAVESICAL THERAPY
2. ROLE OF RANDOM AND DIRECTED BIOPSIES
2. INITIAL BLADDER-SPARING APPROACH
VERSUS CYSTECTOMY
3. ROLE OF SECOND RESECTION
4. SUBSTAGING OF T1 PATHOLOGY
5. WHAT ARE
FACTORS?
THE
3. OPTIMAL BCG ADMINISTRATION
IMPORTANT PROGNOSTIC
4. BCG FAILURE
6. UPPER TRACT, PROSTATIC, AND URETHRAL
INVOLVEMENT
5. NEW TREATMENT APPROACHES ON THE
HORIZON
RECOMMENDATIONS
REFERENCES
190
T1 Urothelial Carcinoma of the Bladder
M.A.S. JEWETT
A.M. NIEDER, M. BRAUSI, D. LAMM, M. O’DONNELL,
K. TOMITA, H. WOO
Most superficial stage T1 urothelial bladder cancers
are high grade and appear to grow rapidly with the
potential to not only recur but progress to invasion,
metastases, and death. In this chapter, we have
focused on the elements of treatment success which
we define as disease-free survival with a high quality of life, including bladder sparing where possible.
tumor extension can occur, particularly after BCG
(bacille Calmette-Guérin) therapy with an initial
complete response, and it should be screened for.
The most difficult decision is whether to initiate
intravesical therapy or to recommend radical therapy, usually with cystectomy. Initial intravesical therapy should be BCG but careful follow-up is necessary with the intent to recommend cystectomy for
persistent or recurrent tumor, although some patients
can be managed by salvage intravesical therapy.
Figure 1 is an algorithm for the management of
stage T1 urothelial tumors presenting as new or
recurrent tumors after previous management of
lower stage tumors. Virtually all are high grade histologically and present a serious risk of progression
in stage by invasion or metastases. Timely and
aggressive management of these tumors is essential
to minimize the risk for the patient. Urologists, in
particular, are in a position to make a significant
impact on the overall outcome of patients in this category.
I. DIAGNOSIS AND STAGING
1. TECHNIQUE OF RESECTION
The initial endoscopic evaluation of patients suspected of or documented as having any stage of urothelial bladder cancer should be performed when complete bladder relaxation is assured at the time of
transurethral resection of bladder tumor (TURBT),
even if cystoscopy was previously performed. The
bladder should not be filled to more than one-third
capacity and the entire urothelium should be viewed
to best appreciate the slightly raised, velvety appearance and the poorly-defined margins of CIS. Bladder
distension should be avoided. Instruments for coldcup biopsy should be available with the set-up. General or peripheral (spinal or epidural) anesthesia is
preferable. A bladder diagram (hard copy or electronic) should be completed by the surgeon after a
diagnostic cystoscopy in order to describe the location, appearance (papillary, sessile, flat), size, and
number of tumors (Figure 2). The bladder diagram
should be part of the patient record. Endoscopic photography is also an excellent method of documenting
bladder abnormalities.
The following sections deal with the sequential steps
in the assessment, decision-making, and treatment of
T1 patients. Urologists, pathologists, and radiologists must work together to not only diagnose new or
recurrent tumors but also to accurately assess individual risk of progression and stratify patients for
treatment. The technique of resection is important to
be complete but also to safely provide sufficient tissue for staging and grading. Random and directed
biopsies are frequently indicated. Immediate adjuvant chemotherapy should be used more frequently.
In our opinion, re-resection is mandatory, if the surgeon cannot guarantee that a complete TURBT has
been performed or when muscle is not present in the
pathological specimen. Clinically useful prognostic
factors have been defined to stratify patients by risk
of progression. Substaging of T1 tumors has been
described but remains controversial. Extravesical
191
Figure 1. Algorithm of Steps and Issues in the Management of T1 Urothelial Carcinoma of the Bladder
IVe - intravesical
192
Figure 2. Example of a Bladder Diagram That Could Be Incorporated into a Clinical Record
(courtesy of Dr. Michael O’Donnell)
193
• Tumor in a diverticulum should be biopsied and, if
possible, resected. The appearance of the tumor
should dictate the extent of the resection or biopsy. An exophytic papillary tumor can be resected
with fulguration of its base.
The initial part of the examination should include a
bimanual palpation or examination under anesthesia
with the bladder empty, which should be performed
before and after TUR, especially if bladder invasion
into deep muscle or fat is suspected. The accuracy of
bimanual examination to predict pathological stage
is not well-established. For superficial bladder
tumors, bimanual examination is unlikely to be helpful but its routine practice should be encouraged,
although examination before resection may be omitted. In fact, an additional benefit of bimanual palpation in the male is the opportunity to palpate the
prostate. Prostatic abnormalities should be duly
noted and investigated further as appropriate. The
role of MRI is also not well-defined, but may well
provide a better assessment of the primary tumor
than exam under anesthesia.
• Bladder perforation may occur as a result of the
obturator nerve reflex and the resulting adductor
spasm. Direct local anesthesia of the obturator
nerve in the obturator canal can prevent obturator
nerve reflex. Local anesthesia with 20 to 30 mL of
2% lidocaine will block the nerve for at least 1
hour.
• Directed (as opposed to random) mucosal biopsies
of all suspicious areas of the bladder are mandatory at the time of TURBT, while random biopsies
of normal-appearing urothelium should not be
part of a routine resection of a low or intermediate
grade superficial bladder tumor. (See Section I.2.
Role of Random and Directed Biopsies.)
Endoscopic resection of bladder tumors may be
facilitated with a continuous flow resectoscope.
Maintaining the bladder capacity at approximately
one-third to one-half of the bladder volume allows
excellent visibility and reduces the chance of bladder
perforation during resection, especially in women,
who may have a thin bladder wall. This is particularly advantageous with tumors located on the posterior wall or dome. Video TUR has become the standard procedure in most institutions. This allows
magnification of the field, which is useful for teaching purposes and reducing the surgeon’s exposure to
body fluids.
2. ROLE OF RANDOM AND DIRECTED BIOPSIES
During the initial endoscopic evaluation, the urologist should make a decision regarding the need for
directed (to an area of visible abnormality), selected
site, or random mucosal biopsies. Biopsy is of particular importance in cases with positive cytology,
especially if no residual tumor is visualized in the
bladder.
If selected site biopsies are performed the locations
are usually lateral to each ureteral orifice (2), lateral
walls (2), posterior wall (1), superior wall (1), and
prostate (1). Cold cup biopsies of any erythematous,
velvety, or edematous area suspicious for dysplasia
or CIS should be performed. The prostatic urethra
should be carefully inspected and biopsied in
patients with prior positive cytology and no visible
tumors or CIS. Prostatic biopsy should include representative tissue from the urethra, ducts, and glands.
Larger tumors should be resected in a systematic
fashion by initiating resection at one side and serially removing portions of tumor. Resection sufficient
to obtain muscle in the specimen is necessary for
staging. A separate biopsy of the tumor base that is
free of cautery artifact, such as a cold cup biopsy, can
facilitate a correct pathological diagnosis. Histological fragments of the tumor and tumor base should be
submitted separately according to depth and surrounding. In general, where possible, all visible
tumor(s) should be completely resected with several
millimeters of the surrounding urothelium and then
fulgurated. A roller electrode can facilitate fulguration. It is essential that the tumor(s) be completely
resected. Some have suggested that this may be
improved by an independent post-resection inspection by a second surgeon (Level 3, [1]). If this crosscontrol is not performed, a final evaluation of the
bladder with a 70° lens is suggested.
Fujimoto et al. prospectively evaluated the usefulness of random bladder biopsies of normal urothelium in patients undergoing TURBT (Level 2, [2]).
The authors identified cancer in only 8 of 100 biopsies, 5 of which were CIS. They concluded that multiple random biopsies are only indicated in patients
with multiple papillary tumors or those with positive
cytology. Van der Meijden et al. retrospectively
reviewed 2 EORTC studies and evaluated the efficacy of random bladder biopsies (Level 3, [3]). Random biopsies of normal-appearing urothelium
demonstrated abnormalities in approximately only
10% of patients (only 3.5% CIS), and thus were
Specific situations in the surgical management of
superficial bladder tumors include the following:
194
thought not to be warranted. Conversely, May et al.
found that random bladder biopsies altered therapy
in 7% of 1033 consecutive patients (Level 2, [4]). In
fact, in 14 patients malignancy was identified in only
the random biopsy and not in the resection of the primary tumor. Importantly, however, these authors
excluded patients with small, primary, solitary bladder tumors. Thus, the committee felt that patients
with tumors that appeared to be of low risk in terms
of appearance, and with negative cytology, should
not undergo random biopsy.
initial and subsequent resection was variable, and it
is not certain that a complete resection was attempted initially. Dutta et al. similarly reported a 64% risk
of understaging T1 lesions when muscle was absent
compared to only 30% when muscle was present in
the TURBT specimens (Level 3, [7]).
Other authors have found that a primary resection of
a T1 bladder tumor may be inadequate to remove all
tumors. Zurkirchen et al. retrospectively reviewed
those patients who underwent follow-up TURBTs
within 6 weeks of their initial resections (Level 3,
[8]). Thirty-seven percent of patients with initially
diagnosed T1 bladder tumors had persistent tumors
on second resection. Grimm et al. similarly retrospectively reviewed 83 patients who underwent
repeat TURBT a mean of 7 weeks after initial
TURBT (Level 3, [9]). Residual tumor was found in
33% of cases, including 53% of those with initially
diagnosed T1 bladder tumors. On univariate analysis, both tumor stage and grade were identified as
predictive for residual tumor on restaging TURBT.
Furthermore, after 5 years there was a significant
decrease in disease-free survival between those who
underwent a second TURBT and those who did not
(63% and 40%, respectively). Brauers et al. evaluated 42 patients with moderate or high grade T1 bladder tumors and reported that 24% of patients were
upstaged to T2 or Tis on restaging TURBT (Level 3,
[6]). Schips et al. prospectively evaluated the findings at first and second TURBT for patients with
high grade T1 bladder tumors and also found residual disease in over 50% of patients (Level 3, [10]).
Both multifocality and tumor grade increased the
risk of finding residual tumor on second TURBT.
While 76% of patients with a solitary T1 lesion at
first TURBT had a negative second TURBT, only
53% of those with multifocal T1 lesions had a negative repeat TURBT. Moreover, 73% of those with
papillary-appearing T1 lesions at first resection had a
negative repeat TURBT, compared to only 47% of
those with solid-appearing T1 lesions.
3. ROLE OF SECOND RESECTION
The diagnosis and management of superficial bladder cancer are dependent upon an adequate TURBT.
The risk of residual tumor being present following
initial transurethral resection of T1 tumors has been
reported to be as high as 60% (Table 1). Most significantly for high grade T1 lesions, it is incumbent
on the urologist to ensure that the tumor is actually
not muscle-invasive, since this typically changes the
treatment options.
Table 1. Understaging in High-risk Non-muscle-invasive
Urothelial Carcinoma of the Bladder [5]
Series
Year
Understaged
Pagano
1991
35%
Amling
1994
37%
Soloway
1994
36%
Freeman
1995
34%
Ghoneim
1997
62%
Stein
2000
39%
Cookson
2001
40%
Stein JP. Sem Urol Oncol 2000; 18:289-295. [5]
Herr retrospectively evaluated the concordance of
the pathological diagnoses between an initial resection and a second TURBT in 150 patients (Level 3,
[6]). The results of the second resection changed the
treatment in 33% of the patients. He importantly
noted the inability to accurately diagnose T1 tumors
without muscle in the specimen. Of 23 patients with
T1 lesions without muscle in the primary resection,
11 (49%) were upstaged to T2 lesions after review of
the second TURBT specimen. However, in this study
different urologists performed the first and second
TURBTs, different pathologists read the first and
second bladder tumor specimens, the time between
Early repeat TURBT can be justified for the purposes of identifying understaged T2 tumors that would
benefit from prompt treatment with cystectomy. In a
series of 189 patients who underwent cystectomy
within 3 months of diagnosis of muscle-invasive disease, there was a significantly better 5-year progression-free survival than if cystectomy was performed
more than 3 months following diagnosis (55% and
34%, respectively) (Level 3, [11]).
195
Summary
of invasion and thus substage the T1 tumors in only
58% of 170 cases. The 5-year recurrence-free survivals for those with T1a and T1b tumors were 86%
and 52%, respectively. This difference was independent of tumor grade.
These studies show that the risk of upstaging on
second TURBT is at least 30% if muscle is present
in the specimen and even higher if muscle is not
present (Level 3). [7,12] Further, the risk of residual tumor on second TURBT is also significant.
Even for solitary, papillary-appearing tumors, the
risk is 24% to 27% [9, Level 3; 10, Level 2; 8, Level
3] Because of these significant rates, it is recommended that a second TURBT be considered for
all patients with high grade Ta or any T1 urothelial carcinoma. This definitive recommendation
was difficult for the authors to make, but even
experienced surgeons have felt that resection was
complete only to find a recurrence, possibly of
higher stage, in exactly the same site a short time
later. Therefore, we believe that a standard of universal re-resection for high grade or T1 tumors
should be recommended in an attempt to prevent
understaging and possible progression to metastatic disease. Although no evidence regarding the timing of a second TURBT is available, the consensus opinion is that this should be performed within 1 to 4 weeks following the initial resection.
Smits et al. further categorized T1 cancers into T1a,
T1b, and T1c (up to, in, and beyond the muscularis
mucosae, respectively) and retrospectively evaluated
the risk of recurrence and progression among the 3
groups (Level 3, [16]). There was no difference in
the 3-year risk of recurrence among the groups.
However, the risks of progression were 6%, 33%,
and 55%, respectively. Furthermore, the combination
of T1c and CIS increased the risk of progression 27
times that of those without T1c and CIS.
Cheng et al. applied a different method to substage
T1 tumors, to obviate the difficulty in identifying the
muscularis mucosae level (Level 3, [17]). They retrospectively reviewed 55 patients with T1 bladder
cancer and compared their TURBT pathology to
their pathology at cystectomy, a median 10 days
from TURBT. All TURBT specimens were evaluated for depth of stromal invasion—as measured by
micrometer from the basement membrane to the
deepest tumor cells. There was a significant correlation between the depth of invasion in the TURBT
specimen and the final pathological stage at cystectomy. Using a cutoff of 1.5 mm depth of invasion,
the sensitivity, specificity, and positive and negative
predictive values for predicting advanced stage disease (>T2) were 81%, 83%, 95%, and 56%, respectively.
4. SUBSTAGING OF T1 PATHOLOGY
Multiple authors have attempted to substage T1 bladder cancers based on the presence of invasion of the
muscularis mucosae. Holmang et al. retrospectively
reviewed 121 stage T1 bladder cancers and evaluated whether the tumors invaded above the level of the
muscularis mucosae (stage T1a) or invaded into and
beyond it (stage T1b) (Level 3, [13]). T1a disease
was found in 54% of patients and T1b in 40%; only
6% of patients could not be pathologically substaged. Stage T1b tumors were significantly higher
grade than T1a tumors; 58% of those with grade 3
T1b tumors ultimately progressed to muscle-invasive disease compared to only 36% with grade 3 T1a
tumors. The 5-year overall survivals for T1a and T1b
tumors were 54% and 42%, respectively. Hasui et al.
similarly reported a worse prognosis for T1 patients
with muscularis mucosae invasion (Level 3, [14]).
With a mean follow-up of 78 months, the progression rates for T1a and T1b cancers were 7% and
54%, respectively. Moreover, the increased risk of
progression was seen regardless of the grade, size, or
multifocality of the tumor. Angulo et al. also substaged T1 cancers based upon the invasion of the
muscularis mucosae (Level 3, [15]). Importantly,
they reported that they were able to assess the level
Bernardini et al. retrospectively evaluated 94
patients with Ta tumors and compared their substage
level with p53 status (Level 3, [18]). Overexpression
of p53 was identified in 26% of patients with T1a
tumors, compared to 53% of patients with T1b
tumors (P < 0.02). Multivariate analysis demonstrated that patients with T1b tumors and CIS had a 7.5
times greater risk of progression than those with T1a
tumors and CIS (P < 0.001).
Kondylis et al. retrospectively evaluated whether the
response to BCG was different in those with T1a and
T1b tumors (Level 3, [19]). At a median follow-up
of 71 months, the incidence of recurrence was noted
in 69% with T1a tumors compared to 65% of T1b
tumors (P = 0.7). Furthermore, progression was
noted in 22% of T1a tumors and 29% of T1b tumors
(P = 0.5). The authors thus concluded that response
to intravesical therapy is not dependent upon T1 substage.
196
tumors but in no low grade tumors (Level 3, [24]).
Tumors with mutant p53 inactivate transcription of
p21 and the Bax gene (Level 3, [25]). Saint et al.
reported that pretreatment p53 nuclear overexpression in superficial bladder tumors is associated with
a high risk of disease recurrence, progression, and
cancer death after BCG therapy (Level 3, [26]).
Alterations of p53 were associated with BCG failure.
Others have not noted that p53 expression before
BCG treatment correlated with BCG failure (Level 3,
[27]). Controversial results have also been reported
in regard to p53 expression as an independent predictor of progression. In a case-control study, Llopis
et al. showed that p53 expression analyzed at a cutoff of 20% positivity is a significant predictor of progression (Level 3, [28]). Steiner et al. did not find
p53 status helpful in the selection of candidates for
radical therapy (Level 3, [29,30]). Lopez-Beltran et
al. reported a number of cell cycle regulators that
appear to be independent predictors of survival of
patients with T1G3 bladder cancer including
p27kip1 and the cyclins D1 and D3 (Level 3, [31]).
Summary
Though authors have reported on the utility of substaging T1 tumors, there is no general consensus
among pathologists regarding the presence of the
muscularis mucosae. Furthermore, randomized
studies have not validated more aggressive treatment for those with deeper T1 lesions. The consensus is that T1 substaging is not yet a validated
prognostic factor.
5. WHAT ARE
FACTORS?
THE
IMPORTANT PROGNOSTIC
The most useful predictors of progression in patients
with stage T1 urothelial carcinoma are clinical,
including histopathology. Traditional factors to predict clinical outcome of T1 urothelial bladder carcinoma following initial TURBT include early recurrence, grade, multiplicity, tumor extent and size, concomitant carcinoma in situ, urothelial carcinoma
involving the prostatic mucosa or ducts, and depth of
lamina propria invasion (Level 3, [17,20,21]). The
response to intravesical therapy is a reliable predictor of progression within 9 months (Level 3, [22]).
Solsona et al. reported that the 80% of patients who
did not achieve a complete response by 3 months had
progression (Level 3, [21]). In addition, this study
indicates that high grade tumor, associated carcinoma in situ, or prostatic mucosal/duct involvement
represent significant pathological predictors of progression. The relative importance of clinical and
pathologic factors varies according to adjuvant therapy. For example, substaging of T1 has not been
found to be useful in BCG-treated patients, and
recurrence or persistence of disease that is downstaged or downgraded may be evidence of response
in an individual patient. Nevertheless, it has been
recognized that these prognostic factors are not accurate enough to predict individual clinical behavior of
T1 urothelial tumors. Therefore, more reliable indicators of biological aggressiveness are needed.
Many other prognostic factors, including genetic
alterations, cell adhesion molecules, a family of proteases, growth factors, and other molecular markers,
have been studied, but to date do not have enough
specificity for clinical use for T1 bladder cancer.
Summary
Useful clinical prognostic factors for T1 urothelial bladder cancer include tumor grade, early
recurrence, multiplicity, tumor size, concomitant
carcinoma in situ, urothelial carcinoma involving the prostatic mucosa or ducts, and depth of
lamina propria invasion. The response to intravesical therapy is a very useful clinical marker
(Level 3) [17,20,21]. A great number of molecular
and genetic prognostic markers including alterations of p53 have been studied for T1 bladder
cancer. However, most of these markers have not
been validated and are not available for clinical
use.
6. UPPER TRACT, PROSTATIC, AND URETHRAL
INVOLVEMENT
A number of molecular prognostic markers have
been reported for T1 bladder cancer (see Chapter 2:
Tumor Markers Beyond Cytology). It has been suggested that alterations of cell cycle regulatory proteins involved in the progression from G1 to S phase
are among the most promising markers (Level 3,
[23]). The p53 tumor suppressor gene is commonly
altered in human malignancies. Pfister et al.
observed mutant p53 in 66% of stage T1 high grade
The overall risk of upper urinary tract urothelial carcinoma (UUTUC) occurrence in patients with superficial bladder cancer is low, ranging from 2% to 4%
(Level 3, [32]). However, this risk is higher in
patients with high grade and superficially invasive
urothelial carcinoma of the bladder, ranging from
13% to 29% (Level 3, [33,34]). Herr et al. found a
197
7% incidence at 5 years after treatment for superficial urothelial carcinoma of the bladder, rising gradually with time to as high as 21% at 15 years (Level
3, [32]). Lifelong observation of the upper urinary
tracts in such patients is recommended. Hurle et al.
reported that patients with UUTUC developing after
treatment of superficial bladder cancer could be
stratified into 3 groups (Level 3, [35]). Those with
primary, solitary, low grade (G1-G2) and low stage
(Ta-T1) superficial bladder cancer (n = 216) were
considered at low risk for disease recurrence or progression and were treated with transurethral resection (TUR) alone. Patients with recurrent or multifocal superficial bladder cancer (n = 182) were considered at intermediate risk and treated with adjuvant
intravesical chemotherapy, and 193 patients with
CIS, high grade (G3) superficial bladder cancer, or
intravesical chemotherapy failure were considered at
high risk and treated with BCG. After a median follow-up of 86 months, 2 (0.9%) of 216 patients at low
risk, 4 (2.2%) of 182 patients at intermediate risk,
and 19 (9.8%) of 193 patients at high risk developed
UUTUC. The incidence of UUTUC is significantly
higher in patients at high risk compared to those at
low risk (P = 0.0004, odds ratio 11.6) and at intermediate risk (P = 0.004, odds ratio 4.8). In addition,
80% of stage pT2-pT3 UUTUC, 90% of multiple
UUTUC, and 80% of patients who died from
UUTUC were in the high risk group. These data suggest that UUTUC is not only frequent but also of
high stage and grade and carries a bad prognosis in
patients at high risk. Since UUTUC is often asymptomatic and mortality is high, frequent and lifelong
observation of the upper urinary tract is suggested
with an annual IVU and urinary cytologic examination and urinalysis every 4 months in patients with
superficial bladder cancer at high risk of disease
recurrence or progression. Schwartz et al. reported a
3.1% upper tract recurrence rate in patients with
superficial bladder cancer and 13% in those with
bladder CIS (Level 3, [36]). The high upper tract
recurrence rate in patients with superficial bladder
cancer and CIS has also been confirmed by other
authors (range 15.4%-29%) (Level 3, [33,37]). Hurle
et al. reported that of 51 patients with T1G3 bladder
cancer treated with induction plus maintenance BCG
courses after TUR and followed up for at least 5
years, 7 (13.7%) had extravesical involvement, 5
(9.8%) had an UUTUC, and 3 (7.9%) of 38 had prostatic involvement (1 of 7 had both) (Level 3, [38]).
tract recurrence with tumor cell implantation. Amar
et al. and De Torres Mateos et al. have reported a
higher upper tract recurrence rate in patients with
reflux (6.4%-19.7%), compared with those without
reflux (0.4%-0.9%) (Level 3, [39,40]). However,
these studies were retrospective and do not take into
account possible transient reflux after TUR when
there may be circulating tumor cells or explain unilateral recurrence with bilateral reflux. Solsona et al.
reported no significant differences in the upper tract
recurrence rates of patients with or without reflux
(Level 3, [41]). Nevertheless, VUR may be a weak
etiologic factor, but multifocality and the presence of
CIS seem to be more important etiologic factors.
Solsona et al. also reported that solitary upper urinary tract involvement did not have a negative
impact on the survival of patients with bladder CIS.
However, when associated with prostate involvement, the survival rate was significantly worse compared to those with primary UUTUC.
Vesicoureteral reflux (VUR) after TUR of bladder
cancer has been suggested as a mechanism for upper
Herr et al. have also reported prostatic tumor relapse
in patients with superficial bladder tumors followed
The incidence of concomitant prostatic urethral
involvement with high-risk superficial urothelial carcinoma has been reported to be between 8.7% and
36.0% (Level 3, [42]). In these cases, Schellhammer
et al. reported that no stromal invasion was found,
and 70% of these patients were successfully treated
by BCG instillation therapy (Level 3, [43]).
Progression to the prostate after BCG instillation
therapy was first reported by Catalona et al., who
described 4 patients with prostatic involvement after
BCG therapy (Level 3, [44]). All of these patients
had prostatic ductal or prostatic urethral cancer,
which can be detected by TUR. Sakamoto et al. recommended TUR biopsy to include prostatic tissue at
the 5 and/or 7 o’clock position at the verumontanum
(Level 3, [45]). Herr et al. reported extravesical
recurrence detected by positive urine cytology in
patients who had long-term follow-up after TURBT
and BCG (Level 3, [42]). Among 307 patients, 78
(25%) developed tumors in the upper urinary tract.
Among the 251 men, 61 (24%) had tumors detected
in the prostatic urethra or ducts (pT4). The median
times to detection of an UUTUC or prostatic epithelial tumor were 56 months and 11 months, respectively, and 32% of the UUTUC and 44% of the pT4
relapses were lethal. They concluded that patients
with high-risk superficial bladder tumors who are
treated successfully by a bladder-sparing strategy are
at increased risk for tumor relapse that involves
extravesical mucosa.
198
al. performed a multicenter, randomized trial of 502
patients with newly diagnosed stage Ta or T1 urothelial carcinoma (Level 2, [47]). Those who received
intravesical mitomycin C within 24 hours of TURBT
had a statistically significant decreased risk of tumor
recurrence compared to those who received placebo.
No patients reported chemical cystitis; however, 6%
of those who received a single dose of mitomycin C
reported dysuria and frequency.
for 15 years (Level 3, [46]). They divided tumor
relapses in the prostate into noninvasive (prostatic
urethra and ducts) or invasive (stroma) with intraurethral or direct prostatic invasion. Of the 186
patients, 72 (39%) had relapse in the prostate, including 45 (62%) with noninvasive prostatic tumor and
27 (38%) with stromal invasion. The survival rate
was 82% in patients with prostatic urethra or duct
involvement compared to 48% in those with stromal
invasion. Prostatic stromal invasion was an independent prognostic variable of survival (see Chapter 8:
Urothelial Carcinoma of the Prostate).
Oosterlinck et al. conducted a prospective, multicenter, randomized, placebo-controlled study of 431
patients with superficial urothelial carcinoma comparing a single adjuvant dose of epirubicin (80 mg in
50 mL sterile water) or sterile water (50 mL), within
6 hours after TURBT (Level 2, [48]). At a mean follow-up of 2 years, the overall recurrence rates for
those who received epirubicin compared to water
were 17% and 32%, respectively (P < 0.0001).
Moreover, when evaluated by subgroups, the recurrence rates for those with stage T1 urothelial carcinoma were 23% and 60%, respectively (P = 0.065).
The risk of chemical cystitis was 11.7% among those
who received epirubicin.
During investigation of positive urine cytology,
tumors in the upper urinary tract were detected in
25% and in the prostatic urethra or ducts in 24% with
multiple recurrent papillary tumors and CIS with
long-term follow-up (Level 3, [42]). Prostatic stromal invasion was an independent prognostic predictor of survival in patients with superficial bladder tumors followed for 15 years (Level 3, [46]).
Summary
UUTUC is not only frequent but also of high
stage and grade, with a bad prognosis in patients
in the high-risk group (patients with CIS, high
grade (G3) superficial urothelial carcinoma, or
intravesical chemotherapy failure) (Level 3, [35]).
Since UUTUC is often asymptomatic and mortality is high, periodic lifelong observation of the
upper urinary tract is suggested with appropriate
anatomic imaging (retrograde pyelogram/I
VU/CT/MRI) and urinary cytologic examination
and urinalysis in patients with superficial bladder
cancer with a high risk of disease recurrence or
progression (Level 3, [35]). The high rate of
upper tract and prostate recurrence in superficial
bladder cancer patients with CIS has also been
confirmed by several authors (15.4%-29%) (Level
3, [37,38,42]).
Bouffioux et al. reported the results of 2 EORTC
prospective, multicenter, randomized studies comparing the efficacy of either early versus delayed
mitomycin C or doxorubicin as adjuvant intravesical
therapy (Level 2, [49]). In protocol 30831, patients
were randomized to receive adjuvant mitomycin C
(30 mg in 50 mL saline) either immediately after or
7 to 15 days after TURBT. Instillations were given
every week for 4 weeks and then monthly for 5
months for a total of 9 instillations. After completion
of 9 doses, patients were randomized again to either
maintenance therapy (monthly for 6 months, for a
total of 15 instillations) or no maintenance. Protocol
30832 was identical except that it was a study of
doxorubicin (50 mg) instead of mitomycin C. A total
of 834 patients were eligible for the protocol, 457 in
the mitomycin trial and 377 in the doxorubicin trial.
The final analyses demonstrated that early intravesical therapy (with or without maintenance) is slightly
superior to delayed therapy with maintenance. Furthermore, if early treatment is given, further maintenance therapy is not beneficial. Based on a mean follow-up of 4 years, the progression rate to muscleinvasive disease was 8% to 11% for all patients. Mitomycin C was slightly better tolerated than doxorubicin, with chemical cystitis being reported by 6%
and 9%, respectively.
II. TREATMENT
1. ROLE OF IMMEDIATE ADJUVANT INTRAVESICAL THERAPY
The risk of recurrence of high grade stage T1 urothelial (transitional cell) carcinoma approaches 80%. In
the hopes of reducing this risk, many trials have
investigated the use of prophylactic or adjuvant
intravesical therapy at the time of TURBT. Tolley et
Solsona et al. specifically evaluated the effectiveness
of a single dose of mitomycin C in patients with non-
199
high grade superficial urothelial carcinoma (Level 2,
[50]). Patients were prospectively randomized to
either mitomycin C (30 mg in 50 mL saline) within 6
hours of TURBT or observation (N = 121). Sixtytwo of the patients had stage T1 urothelial carcinoma, grade I or II (all high grade tumors or carcinoma
in situ were excluded). The risks of recurrence during the first 2 years were 16% and 34%, respectively (P = 0.019); however, the overall risks of recurrence were 40% and 54%, respectively (P = 0.115).
Only 2 patients (3.5%) in the mitomycin C group had
chemical cystitis.
nificantly reduces the risk of recurrence of bladder
tumors. They concluded that adjuvant intravesical
therapy is the treatment of choice in patients with a
single, low grade superficial bladder tumor and
should be the initial treatment (prior to subsequent
intravesical BCG) in those with higher risk bladder
tumors.
Summary
These multicenter, randomized, prospective studies
demonstrate that the risk of recurrence can be
reduced by 50% at 2 years and at least 15% at 5
years with a single dose of adjuvant intravesical
chemotherapy [47,48,50]. If mitomycin C is given
within 24 hours of TURBT, maintenance therapy
does not significantly reduce the recurrence risk
further (Level 2, [49]). Because of this significant
decrease in recurrence risk, it is recommended that
a single dose of intravesical chemotherapy be
given ideally within 6 hours but no more than 24
hours following TURBT unless there has been perforation, extensive/deep resection, or intolerance/
allergy to chemotherapy. These recommendations
are exclusively for chemotherapy; BCG should
never be given immediately postoperatively.
Krege et al. performed a prospective, randomized,
multicenter trial comparing TURBT alone versus
TURBT with adjuvant maintenance mitomycin C
(20 mg in 50 mL saline every 2 weeks for 1 year and
then monthly for an additional year) versus maintenance BCG (120 mg in 50 mL saline weekly for 6
weeks and then monthly for 4 months) (Level 2,
[51]). Only 25% of the study patients had stage T1
urothelial carcinoma. At a median follow-up of 20
months, there was a statistically significant decrease
in risk of recurrence for those who received maintenance adjuvant therapy compared to those who did
not. There was no significant difference between
those who received mitomycin C or BCG. Mitomycin C was better tolerated than BCG, with cystitis
being reported by 16% and 34%, respectively.
2. INITIAL BLADDER-SPARING APPROACH
VERSUS CYSTECTOMY
Kurth et al. performed a prospective, multicenter,
randomized trial comparing TURBT alone to
TURBT with adjuvant doxorubicin (50mg in 50 mL
saline) or ethoglucid (1.13 gm in 100 mL water)
(Level 2, [52]). The chemotherapeutic agents were
instilled within 1 week of TURBT and were given
weekly for 1 month and then monthly for 11 months.
The time to first recurrence was significantly greater
in those who received either intravesical therapy
compared to placebo (P < 0.001). These results were
noted for both Ta and T1 lesions. However, no differences were noted between doxorubicin and
ethoglucid. At 3 years, the recurrence-free survivals
for the no therapy group, doxorubicin group, and
ethoglucid group were 29%, 48%, and 56%, respectively. The risks of chemical cystitis were similar for
those receiving doxorubicin or ethoglucid, 2.8% and
3.6%, respectively.
The goal for treatment of bladder cancer is to minimize the morbidity and mortality of the disease while
maximizing the patient’s quality of life. This is particularly true of new or recurrent T1 disease. The
substantial majority of stage T1 bladder cancers are
high grade and therefore at particular risk of progression to incurable metastases. Treatment with
TURBT alone without at least adjuvant intravesical
therapy has an unacceptable risk of recurrence and
progression. Progression in studies of such patients
is as high as 35% to 48% within 3 years (Level 3,
[54-56]). The decision to recommend immediate
cystectomy or intravesical therapy with delayed cystectomy for persistent or recurrent tumor is one of
the most difficult in the management of all stages of
bladder cancer. Quality of life data is interesting in
that patients are willing to accept the disabilities
incurred with cystectomy to avoid compromising
survival if that is the alternative (Level 3, [57]).
Sylvester et al. recently performed a meta-analysis
regarding the efficacy of a single dose of adjuvant
intravesical therapy (Level 1, [53]). The authors evaluated 7 previously published trials on a total of over
1400 patients. The authors found conclusive evidence that a single dose of intravesical therapy sig-
Selection of the treatment strategy for stage T1 bladder cancer requires consideration of the risks and
benefits of cystectomy, repeat transurethral resec-
200
tion, immediate instillation of chemotherapy, and
BCG immunotherapy techniques. As noted above,
repeat resection will reveal that residual or recurrent
disease and even understaging is frequent. When
cystectomy is done for clinical stage T1 disease, as
illustrated in Table 1, 30% or more of patients will
be found to have unsuspected T2 or greater disease.
Cystectomy is therefore an option to be considered,
and the results of cystectomy should be compared
with those of other treatments. In a recent contemporary cystectomy series of 300 patients, the overall 5year survival for patients undergoing cystectomy for
bladder cancer was only 45% [58]. Surprisingly, survival for patients with non-muscle-invasive disease
was not significantly better than that for T2 disease,
64% versus 59%. Aggressive surgery should be justified by objective data, but reports of increased mortality in patients who develop muscle-invasion
requiring cystectomy while on conservative treatment and observation schedules clearly raise concern
about delaying cystectomy.
Table 2. Progression in T1G3 Urothelial Carcinoma of the
Bladder Without the Use of BCG
Author/Year
N
Progression
(%)
Follow-up
(mos)
Heney 1983
27
48
36
Rutt 1985
430
31
60
Malmstrom 1987
7
43
60
Jakse 1987
31
33
60
Kaubisch 1991
18
50
36
Mulders 1994
48
27
48
Klan 1995
17
65
72
Holmang 1997
58
48
84
519
33
Total
Table 3. History of BCG-Treated T1G3 Urothelial Carcinoma of the Bladder
a) Intravesical Therapy
Prior to the advent of BCG immunotherapy, the incidence of progression in high grade, stage T1 urothelial carcinoma, as illustrated in Table 2, ranged from
27% to 65% with follow-up ranging from 36 to 84
months. These poor results and the subsequent confirmation that intravesical chemotherapy fails to
reduce disease progression served as justification for
cystectomy. These data, however, should not be used
to justify cystectomy in the BCG era.
With the advent of BCG, reported results of intravesical therapy in T1 disease, as illustrated in Table 3,
have dramatically improved. With follow-up ranging
from 22 to 78 months, overall progression is in the
range of 12%, varying from 0% to 35%. It is quite
remarkable that the overall incidence of progression
in patients with T1 disease, in the range of 12%, is
less than the incidence of occult muscle-invasive disease (up to 30%) in patients who undergo immediate
cystectomy [59]. Though patients managed by initial intravesical therapy have a high likelihood of
achieving a complete remission, there is some data
indicating that the longer-term risks of progression
are greater. Cookson et al. reported that after 15
years of follow-up, 53% of patients with initial highrisk superficial bladder cancer progressed to muscleinvasive disease, 36% eventually underwent cystectomy, and 34% were dead of bladder cancer (Level 3,
[60]). Only 27% were alive with an intact bladder.
Similar results have been reported by Shahin et al.
with 153 patients managed by either TURBT and
201
Author/Year
N
Progression
(%)
Follow-up
(mos)
Boccon-Gibod 1989
47
21
14-64
Dal Bo 1990
24
25
22
Samodi 1991
62
0
46
Cookson 1992
16
19
59
Eure 1992
30
7
39
Pfister 1995
26
27
54
Hurle 1996
51
14
33
Zhang 1996
23
35
45
Serretta 1996
50
12
52
Vicente 1996
95
11
46
Lebret 1998
35
12
45
Baniel 1998
78
8
56
Klan 1998
109
13
78
Gohji 1999
25
4
63
Brake 2000
44
16
43
Pansadoro 2002
81
15
76
Total
796
12
BCG or TURBT alone (Level 3, [61]). At a median
follow-up of 5.3 years, disease recurred in 70% and
75% of patients treated with BCG and TURBT
alone, respectively. Progression was seen in 33% and
36%, respectively. Deferred cystectomy was performed in 29% and 31%, respectively. Overall and
disease-specific survival for those receiving BCG
compared to TURBT alone was 42% and 77% versus
48% and 79%, respectively. The authors stated that
BCG therapy is unlikely to substantially alter the
final outcome for patients with high grade T1 urothelial carcinoma.
CIS in the analysis of risk factors for progression. In
this combined group of patients, the 3-month clinical
response was a highly predictive factor for the development of progression. A lack of response at the 3month evaluation was associated with an 82.3%
chance of progression.
b) Cystectomy
The disease-specific survival after cystectomy for
superficial urothelial carcinoma is higher than that
for patients with muscle-invasive disease, but it is
not 100%, largely due to understaging. As well, the
benefits must be balanced by the morbidity and mortality of the surgery. Amling et al. reported on a large
series of 531 patients undergoing cystectomy and
found a 2.3% perioperative mortality and a 20.5%
rate of complications (Level 3, [65]). Similar rates of
complications have been reported in other large cystectomy series by Stein et al. and Ghoneim et al.
(Level 3, [59,66]).
There are side effects with intravesical therapy. Up to
90% of patients experience irritative lower urinary
tract symptoms and a small number of patients have
serious, debilitating complications such as sepsis and
contracted bladders. Lamm et al. reported that only
16% of patients were able to tolerate a full maintenance course of BCG secondary to adverse effects,
albeit in an earlier era (Level 2, [62]).
Experience with immediate cystectomy following
restaging TURBT for multifocal disease, difficulty
of endoscopic access for resection, associated CIS,
and visually incomplete resection has been reported.
This consensus report is perhaps the only one to
attempt to stratify risk as a guide to management
with radical cystectomy versus endoscopic resection
(Table 4). The level of evidence to support these proposed risk categories is at levels 3 and 4.
Conservative therapy is an attractive option, given
the known response rates to BCG, in many patients
with bladder cancer, specifically those with comorbid diseases associated with cigarette smoking and
limited life expectancy. Improved BCG treatment
strategies, particularly the use of improved maintenance schedules such as the 3-week SWOG schedule, would be expected to provide even better results
(Level 2, [63]). While young, healthy patients
respond equally well to intravesical immunotherapy,
even with meticulous follow-up patients remain at
long-term risk for recurrence, progression, and death
from bladder cancer. Cystectomy removes not only
the urothelium at risk in the bladder, but also the
prostate and distal ureters, sites where recurrence is
difficult to detect and dangerous. These risks, like
those of cystectomy itself, should be carefully
explained to patients.
Table 4. Risk Categories of T1 Tumors
Low-risk T1
Unifocal disease
No associated carcinoma in situ
Tumors in an accessible part of the bladder
Residual disease less than T1 on restaging TURBT
High-risk T1
Clinical response to intravesical therapy has been
shown to be a factor predictive of progression in the
case of CIS and mixed groups of T1 and CIS or T1
patients alone; a study of patients treated with intravesical doxorubicin found that 50% of those found to
have stage T1 or grade 3 recurrent tumors developed
progression (Level 3, [64]). The pathological stage
of the tumor at recurrence was the only factor predictive of recurrence in this study. Solsona et al.
demonstrated a complete clinical response rate to
intravesical therapy for T1 disease of 78% in 80
patients (Level 3, [21]). However, as in the case of
many studies on high risk superficial bladder cancer,
T1 tumors in this study were not separated out from
Multifocal disease
Associated carcinoma in situ
Tumors located in dome and anterior wall of bladder
Residual disease T1 on restaging TURBT
There is significant support for early cystectomy for
T1 disease in view of the high late failure rate after
initially successful intravesical therapy and the
reported good quality of life after cystectomy [67].
However, the proponents of an aggressive initial
approach acknowledge that a significant number of
202
patients will be rendered disease-free with bladdersparing strategies. Current proposed indications for
immediate surgery include younger patients with T1
tumors with at least one additional bad prognostic
factor including multifocality, associated CIS, prostatic involvement, and tumor at a site difficult to
resect. Bianco et al. performed a multivariate analysis to identify risk factors in patients undergoing cystectomy that influenced cancer-specific survival and
found that patients with concomitant CIS and those
who had persistent disease after an initial course of
BCG therapy were at significant risk (Level 3, [68]).
high grade superficial bladder cancer (Level 3, [70]).
Of 105 out of 226 urologists responding to a survey,
73% would treat Ta and T1 disease that had already
twice failed with BCG with further intravesical therapy. Radical treatment was only selected as an option
by 19% of surveyed urologists. In an older study of
the practices of British urologists, Bower et al.
reported that only 17% would utilize intravesical
therapy and 44% would select radical treatment for a
typical 60-year-old man with high grade T1 bladder
cancer (Level 3, [71]). Although presented with different scenarios, the implication is of possible differences in trans-Atlantic approaches to managing high
grade superficial disease.
Herr and Sogani retrospectively evaluated 90
patients with high-risk superficial bladder cancer
who ultimately underwent cystectomy (Level 3,
[69]). These authors reported improved 15-year disease-specific survival for those who underwent cystectomy within 2 years after initial BCG treatment.
Moreover, those who underwent cystectomy for
recurrent superficial disease had an improved outcome over those who underwent surgery for progressive disease. The authors thus concluded that deferring cystectomy until progression to muscle-invasive
disease may decrease a patient’s overall disease-specific survival. Nevertheless, 217 patients from their
original cohort of 307 with high-risk superficial disease never required cystectomy and were thus spared
the morbidity of cystectomy.
The presence of metastasis has the most profound
impact on survival. A large series of 1054 patients
who had undergone radical cystectomy was retrospectively reviewed by Stein et al. (Level 3, [59]).
The authors identified 401 patients who had pathologically superficial tumors (pT0, pTa, pT1, or pTis).
These patients demonstrated improved 5-year recurrence-free survival compared to those with nonorgan confined tumors (pT3b, pT4, and those with
positive lymph nodes). In fact, no survival differences were observed when comparing superficially
noninvasive (pTa, pTis), lamina propria-invasive
(pT1), and muscle-invasive tumors (pT2, pT3a), as
long as there was no evidence of metastatic disease
to the lymph nodes. The overall recurrence-free survivals in those with organ-confined, node-negative
disease were 85% and 82% at 5 and 10 years, respectively. A total of 246 patients (24%) had lymph node
tumor involvement. The 5- and 10-year recurrencefree survivals for these patients were 35% and 34%,
respectively.
c) Patterns of Care
Joudi et al. reported on the practice patterns of urologists in the United States with the management of
Summary
No prospective, randomized studies have compared immediate cystectomy with conservative
therapy of high grade T1 urothelial carcinomas.
Patients should be offered both and counseled
effectively on the risks and benefits of each,
specifically the risks of progression while receiving conservative therapy compared to the morbidity and mortality of cystectomy with a potential survival benefit for those whose pathology is
low stage. However, no patient should receive
conservative therapy without first undergoing a
repeat TURBT to rule-out understaging.
3. OPTIMAL BCG ADMINISTRATION
The original BCG induction therapy regimen was
devised by Morales et al. in 1976 [72]. This regimen
consisted of 6 weekly doses administered intravesically, as well as a percutaneous dose. Brosman et al.
subsequently published their success with BCG
without a percutaneous dose in 1982, and that has
developed into standard of care treatment [73].
Administration of intravesical BCG before the resection site has begun to reepithelialize may result in
systemic absorption and toxicity;induction therapy
should be delayed for at least 2 weeks from TURBT
[63]. Three months (12 weeks) after the first dose of
induction BCG therapy, the patient should be
brought back for cystoscopy with possible biopsy (if
indicated) and urinary cytology to assess response
and then to make a recommendation about the use of
maintenance therapy.
The only prospective, randomized study evaluating
the efficacy of maintenance BCG was published by
Lamm et al. in 2000. Those in the maintenance BCG
cohort received BCG once a week for 3 successive
203
weeks at 3 and 6 months, and then semiannually for
up to 3 years (Level 2, [63]). With this regimen,
recurrence, as well as progression, was significantly
reduced. Since only 16% of patients received treatment at each of the 7 scheduled maintenance periods
it is anticipated that fewer maintenance treatments
are needed. Reduced maintenance schedules, however, have not been adequately evaluated. Current urological practice includes reduction of the dose of
BCG to 1/3, 1/10, 1/30, and even 1/100 dose to prevent increasing side effects. Additional studies are
evaluating the role of adding interferon. A metanalysis of reports of maintenance therapy also supports
its use to not only reduce the risk of recurrence but to
reduce the risk of progression [74].
included all patients who received 1 or more courses
of BCG [101-103]. Investigators have often combined patients with persistent disease (nonresponders) and patients with recurrent disease after an initial response [98,100], and a few studies have combined patients who were nonresponders to BCG and
patients who could not complete BCG therapy
because of toxicity (BCG-intolerant) [100,101]. Furthermore, many studies have combined all patients
with papillary tumors with and without CIS. Finally,
most studies did not indicate the disease-free interval
after the last BCG course. These inconsistencies
have led to comparisons of outcome in a very heterogeneous population.
In the most general sense, any recurrent disease after
initiation of BCG therapy can be referred to as “BCG
failure.” However, to provide more uniformity in
reporting, the following alternative descriptive terms
for specific types of BCG failure should be used
whenever possible:
4. BCG FAILURE
a) Scope of the Problem
Although BCG is a highly-effective therapy for bladder cancer, the problem of BCG failure is significant.
Indeed, approximately 40% to 50% of patients with
T1 disease treated with BCG will either fail to
respond or relapse with recurrent disease, usually
within the first 5 years (Table 5) [38,61,75-96]. The
progression rate for these patients during this same
time is usually between 15% and 20% but can vary
between 7% and 50%, depending on particular circumstances where size, high grade, and concurrent
CIS are further adverse prognostic variables and
understaging is a recognized problem. Studies
employing more intensive BCG retreatment and
extended BCG maintenance schedules tend to show
better results. The median time to progression generally exceeds 12 months with an estimated progression rate of 5% or less by 6 months [91]. For these
patients, radical cystectomy is still the gold standard.
However, patients are sometimes reluctant to undergo major surgery for a condition that does not pose
an immediate threat to their lives. Furthermore, radical cystectomy is not suitable for a subset of patients
with severe comorbidities. A number of alternatives
have thus been developed.
BCG-REFRACTORY: Failure to achieve a disease free
state by 6 months after initial BCG therapy with
either maintenance or re-treatment at 3 months due
to either persistent or rapidly recurrent disease [97].
Also includes any progression in stage, grade, or disease extent by 3 months after first cycle of BCG, i.e.
non-improving or worsening disease despite BCG.
BCG-RESISTANT: Recurrence or persistence of disease at 3 months after induction cycle but of lesser
degree, stage, or grade that is no longer present at 6
months from BCG retreatment +/- TUR, i.e. disease
improves then resolves with further BCG.
BCG-RELAPSING: Recurrence of disease after
achieving a disease-free status by 6 months, i.e. disease resolves after BCG then returns. Relapse is further defined by time of recurrence as early (within 12
months), intermediate (12-24 months), or late (>24
months). Caution: relapsing disease while on active
maintenance (within 3 months) may qualify as BCGrefractory.
BCG-INTOLERANT: Disease recurrence after a less
than adequate course of therapy is applied due to a
serious adverse event or symptomatic intolerance
that mandates discontinuation of further BCG, i.e.
recurrent disease in setting of inadequate BCG treatment due to drug toxicity.
b) Defining BCG Failure
In evaluating salvage therapies for use after BCG
failure, Herr and Dalbagni aptly noted that comparisons between therapies have been hampered by the
lack of standard definitions for BCG failure and
BCG-refractory urothelial carcinoma (TCC) [97].
Some series have defined BCG failure after a single
induction course of BCG [98,99], others after 2
courses [100]. In addition, the methods of reporting
the results have been inconsistent. Most studies have
c) Treatment Options
CYSTECTOMY. There is great variation in practice
patterns as to the timing of cystectomy in patients
who fail induction BCG therapy. These vary from
204
derivative valrubicin. Of 90 valrubicin-treated
patients with CIS +/- papillary urothelial carcinoma
who had failed at least 2 cycles of prior intravesical
therapy, most commonly BCG, only 21% had a complete response at 6 months and 8% by 24 months
[107]. Notably, all 5 patients with stage T1 disease
(previously resected) plus CIS failed to achieve a
complete response. Given these poor results, it
appears that current intravesical salvage chemotherapy has little to offer patients failing BCG, especially with stage T1 disease.
immediate surgery after the first follow-up cystoscopy if there is residual disease to delaying until 6
months if a complete response is not achieved. The
evidence for this interval is not well-established at
the present time. There is general consensus that the
prognosis for some patients with aggressive disease
can be adversely affected by delayed surgery, but the
difficulty is in predicting this risk for the individual.
Therefore, alternative bladder-sparing strategies are
frequently employed and include the following.
REPEAT BCG TREATMENT. Possibly appropriate for
both BCG-resistant and BCG-relapsing disease, the
success of a second course of BCG for stage T1 disease has not been extensively reported and only a
few published studies have addressed this issue.
Cookson et al. reported an initial 69% (59/86) complete response to BCG in patients with any grade T1
disease and then another 70% (19/27) responded to
further TUR and BCG including 64% (7/11) with
recurrent T1 disease [77]. Similar results were
reported by Brake who found a 70% (89/128) enduring response after 1 BCG cycle and 51% (19/37) for
the remaining 37 patients (13 of whom had already
progressed) [89]. Pansadoro et al. reported that the
response rate of 47 patients to TUR plus one cycle of
6 weekly BCG instillations was 53% (25/47) [104].
Of the 22 failures treated with repeat TUR and a second cycle of BCG, 27% (6/22) responded, and, of the
remaining 16 patients who received a third cycle of
BCG, only 6% (1/16) responded. These results are
similar to those reported from BCG studies in nonT1 restricted tumors and illustrate that a second (but
not greater) course of BCG may be appropriate in
select patients with original stage T1 disease who
recur with non-BCG-refractory disease [105]. Unfortunately, there is insufficient data to assess the effectiveness of repeated BCG treatments in refractory
patients or those with recurrent T1 disease.
INTERFERON-ALPHA IMMUNOTHERAPY. Two observations suggest that IFN−α is unlikely to be of benefit in stage T1 BCG failures. The long-term (> 2
year) success rate of IFN−α monotherapy of BCG
failure patients (CIS and/or papillary TCC) is generally under 15% [108]. Furthermore, in a study of
IFN−α monotherapy for primary stage T1 disease,
IFN−α was found to be no better than placebo at 43
months follow-up [109].
−α. Several single
COMBINATION BCG PLUS IFN−
institutional studies have demonstrated that the combination of low-dose BCG plus IFN−α may be useful as a salvage regimen in BCG failures [102,
103,110,111]. With follow-up ranging from 12 to 30
months, disease-free rates were in the range of 50%
to 60%, even in patients with recurrent T1 disease.
Furthermore, no patient having an expedient cystectomy after BCG plus IFN-α failure had unresectable
or metastatic disease. Interim results of an even larger group of 231 BCG failure patients in a multi-institutional study have reported a 42% freedom from
disease rate at 24-month median follow-up [112].
The efficacy results for stage T1 patients have not yet
been published, but preliminary analysis reveals a
similar degree of durable response among an approximate 10% progression rate (M. O’Donnell, personal
communication).
INTRAVESICAL SALVAGE CHEMOTHERAPY. Of the
various standard intravesical chemotherapeutic
agents (thiotepa, doxorubicin, mitomycin C) there is
only minimal reported experience with their use in
patients failing prior BCG. Malmstrom reported a
19% 3-year disease-free rate among intermediateand high-risk patients treated with mitomycin C who
had failed a prior first induction cycle of BCG [106].
The results for T1 recurrences are unknown. Similarly, there is little data on the newer anthracycline
OTHER ALTERNATIVES. There is no reliable data published on the use of photodynamic therapy for recurrent stage T1 cancer though it is generally felt to be
more effective on surface disease such as CIS [113].
Likewise, although 5-year disease-free survivals of
50% to 60% for radiation therapy for stage T1 disease have been reported, its role as a salvage for
BCG failures is not established [114]. Furthermore,
for T1 disease alone, local recurrence or progression
occurs in approximately 50% [115].
205
206
Table 5. Results of TUR and BCG Therapy for Stage T1 Tumors
207
Table 5. Results of TUR and BCG Therapy for Stage T1 Tumors (Continued)
Electromotive intravesical mitomycin C (eMMC)
has been proposed to improve drug delivery across
biological membranes with increased accumulation
in bladder tissue. Di Stasi et al. randomized 3 groups
of patients with CIS to 40 mg eMMC instillation
with 20 mA electric current for 30 minutes, 40 mg
passive mitomycin C with a dwell time of 60 minutes
or 81 mg BCG with a dwell time of 120 minutes
[118]. Patients were scheduled for an initial 6 weekly treatments, a further 6 weekly treatments for nonresponders, and a follow-up 10 monthly treatments
for responders. There was a statistically significant
superior complete response rate at 6 months for
eMMC (58%) compared to passive mitomycin C
(31%). The response rate of eMMC approached that
of BCG (64%). Peak plasma mitomycin C was significantly higher following eMMC than after passive
mitomycin C (43 vs. 8 ng/mL), supporting the
hypothesis that electromotive MMC increases tissue
levels.
Summary
The failure rate of stage T1 disease treated with
initial TUR and one cycle of 6 weekly instillations
of BCG is significant. The threat of progression
remains real but comfortably low enough within
the first 6 months of beginning BCG to consider
alterna tives to cystectomy for those patients unfit
or refusing this standard management option.
Defining the type of BCG failure may be helpful
in deciding about conservative treatment strategies
where BCG-refractory disease has less of a margin
for tolerating treatment-related delays. However,
no formal studies studying patterns of BCG failure
are yet available for review. The current best
option for alternative treatment includes re-resection and repeat BCG, possibly with interferonalpha as a costimulant. There is no reported evidence of significant efficacy using current intravesical chemotherapy, interferon-alpha monotherapy, photodynamic therapy, or radiation therapy.
b) Sequential Drug Therapy
Alternative approaches have been investigated to
improve the efficacy of intravesical therapy. Several
investigators have explored the use of BCG combined with chemotherapy. The rationale for giving
chemotherapy prior to BCG is to induce sloughing of
the urothelium, allowing BCG to better interact with
fibronectin and initiating an immune response. However, BCG immediately after epirubicin is not welltolerated. Erol reported that over a third of patients
discontinued treatment due to severe cystitis [119].
5. NEW TREATMENT APPROACHES ON THE
HORIZON
a) Technological Advances in
Chemotherapeutic Drug Delivery
Intravesical
Better delivery of standard intravesical chemotherapeutic agents has the potential to improve outcome in
high-risk patients. Currently there are 2 competing
technologies undergoing clinical trials that may
result in resurgence in the use of intravesical
chemotherapy.
Rintala et al. reported a novel approach of alternating
mitomycin C and BCG for prophylaxis of superficial
papillary bladder cancer [120]. After an induction
course of mitomycin C, 188 patients with recurring
Ta and T1 tumors were randomly assigned to maintenance mitomycin C versus alternating mitomycin
C and BCG instillations (Pasteur Strain). The
patients were treated for 2 years, and the mean follow-up was 34 months. Alternating mitomycin C and
BCG was equal in efficacy to mitomycin C and was
clearly superior to transurethral resection alone. For
CIS, Rintala et al. reported that alternating BCG with
mitomycin C was superior to mitomycin C alone
[121]. The superiority of BCG and mitomycin C
could, however, be attributed to the presence of BCG
in one arm and not the other rather than the alternating mode of delivery. More importantly, no significant side effects developed in the alternating group.
A different randomized prospective trial of sequential BCG and eMMC was reported by DiStasi et al.
[122]. Compared to 6 weekly BCG instillations fol-
Local microwave hyperthermia in conjunction with
mitomycin C (20mg/50mL) was compared in a multicenter randomized trial to intravesical mitomycin C
alone in 83 patients [116]. Hyperthermia was delivered at a temperature of 42°C for at least 40 minutes.
At a minimum follow-up of 24 months, there was a
statistically significant reduction in recurrences
between the 2 groups (17.1% for chemothermotherapy vs. 57.5% for chemotherapy alone). This modality has also been used in treating patients with high
grade superficial bladder cancer (Ta or T1, G3) as a
prophylactic (40 mg mitomycin C) or ablative (80
mg mitomycin C) protocol by Gofrit et al. [117] In
24 patients administered the prophylactic protocol,
62.5% were recurrence-free after a mean follow-up
of 35.3 months. The ablative protocol was administered to 28 patients with complete ablation of the
tumor in 75% and a recurrence free rate of 80.9% at
a mean follow-up of 20 months.
208
lowed by 1 year of monthly maintenance, a program
of BCG, BCG, then eMMC times 3 for weekly
induction and eMMC, eMMC, then BCG times 3 for
monthly maintenance resulted in a statistically significant decrease in recurrence at 5 to 6 years from
47% to 28%. In contrast, Kaasinen reported that
alternating BCG with interferon-alpha after an
induction course of mitomycin C was inferior to
BCG after mitomycin C [123].
both first- and second-line, single-agent therapy for
the treatment of metastatic urothelial carcinoma
[129,130]. Studies have reported a low incidence of
systemic side effects. A randomized, multicenter,
phase 3 study demonstrated that patients with unresectable or metastatic disease treated with gemcitabine plus cisplatin (GC) had a similar survival to
patients treated with MVAC (methotrexate, vinblastine, doxorubicin [Adriamycin], and cisplatin), and
GC had a better safety profile and tolerability [131].
Based on its excellent clinical activity, patient tolerability, and chemical characteristics, gemcitabine
represents a logical candidate for intravesical therapy.
A randomized phase 3 trial of intermediate- and
high-risk superficial bladder cancer comparing
sequential mitomycin C for 4 weeks followed by
weekly BCG versus weekly mitomycin C showed no
difference in recurrence or progression [124]. BCG
alternating with epirubicin was not superior to BCG
alone, but had fewer side effects [125].
Dalbagni et al. reported a phase 1 study of intravesical gemcitabine twice a week for 3 weeks, followed
by a second cycle after a week of rest, in a heavily
pretreated population with BCG-refractory urothelial
carcinoma. This study demonstrated that intravesical
gemcitabine was well tolerated with minimal bladder
irritation and acceptable myelosuppression. Serum
levels of gemcitabine were undetectable at concentrations of 5 mg/mL, 10 mg/mL, and 15 mg/mL.
However, serum gemcitabine was detected at a concentration of 20 mg/mL. Complete response, as
defined by a negative posttreatment cystoscopy
including a biopsy of the urothelium and a negative
cytology, was achieved in 7 of 18 patients (39%)
[101]. This was followed by a phase 2 study of
patients with BCG-refractory urothelial carcinoma to
determine the efficacy of gemcitabine as an intravesical agent. Twenty-eight patients completed therapy,
and 16 achieved a complete response [132].
BCG monotherapy was superior to an induction
course of mitomycin C followed by alternating mitomycin C and BCG instillations in patients with Tis
disease [126]. The recurrence-free survival and progression-free survival were also superior in the
patients treated with BCG only.
Serrata et al. has reported using adjuvant sequential
mitomycin C and epirubicin in 91 of 137 patients
with T1G3 bladder cancer after initial TUR [127].
With close to 20 years of follow-up, the overall
recurrence rate was 51%, but significantly less in the
sequential chemotherapy protocol. The overall progression rate of 9.5% was no different. Only 7% of
patients died of bladder cancer, and the cystectomy
rate was also 7%.
As yet it is not possible to determine whether mixed
chemotherapy or chemoimmunotherapy programs
will dependably result in improved outcomes.
Laufer et al. reported a phase 1 study of weekly
intravesical gemcitabine in 15 patients who received
prior intravesical therapy. Serum gemcitabine levels
were undetected at concentrations of 5 mg/mL, 10
mg/mL, 15 mg/mL, and 20 mg/mL, while low concentrations were present in all patients receiving 40
mg/mL. However, the metabolite dFdU (2’2’-difluorodeoxyuridine) was detectable in the plasma of
patients receiving gemcitabine at concentrations of
15 mg/mL or higher, implying minimal absorption of
gemcitabine at lower doses. The authors concluded
that intravesical gemcitabine is well-tolerated, with
minimal toxicity. Furthermore, no evidence of recurrence at 12 weeks was noted in 9 of 13 evaluable
patients [133].
c) New Chemotherapeutic Drugs for Intravesical
Use
Gemcitabine (2’,2’-difluoro-2’-deoxycytidine) is a
novel deoxycytidine analog with a broad spectrum of
antitumor activity. Gemcitabine has a molecular
weight of 299.66 kD, and, after intracellular activation, the active metabolite is incorporated into DNA,
resulting in inhibition of further DNA synthesis.
Gemcitabine may also inhibit ribonucleotide reductase and cytidine deaminase as part of its cytotoxic
activity [128]. Unlike most other chemotherapeutic
agents, gemcitabine has no vesicant (tissue-irritating) properties, suggesting it may be better tolerated
in the bladder.
In a recent phase 1 study, De Berardinis reported no
systemic detection of gemcitabine at a concentration
of 40 mg/mL. However, the inactive metabolite was
detected in plasma. They were able to demonstrate
Gemcitabine is highly effective (overall response
rates ranging from 22.5%-28%) and well tolerated as
209
clinical trials [141,142]. Cell-based immunotherapy
is also under study with delivery of activated tumoricidal macrophages into the bladder [143]. Studies
with agents that target specific growth factor-related
signaling pathways are also underway [144].
activity of deoxycytidine kinase in tissue samples, an
enzyme that produces 2’,2’-difluoro-deoxycytidine
triphosphate, the active metabolite of gemcitabine
[134]. Palou et al. similarly showed excellent tolerability and little absorption with a single dose of gemcitabine immediately post-TUR [135].
Summary
The chemoablative activity of intravesical gemcitabine was recently reported in a marker lesion
study in patients with papillary Ta or T1 grade 1 or 2
disease [136]. With a sample size of 39 patients,
2000 mg of gemcitabine in 50 mL saline given weekly for 6 weeks resulted in complete ablation of 56%
of the marker lesions.
There are several developments underway for
superficial bladder cancer therapy that are likely
to emerge as practical alternatives in the near
future. Among the most developed are the new
technology machines using microwave or electrical energy to facilitate chemotherapeutic drug
transport into the bladder wall. Among new
chemotherapeutic drugs, intravesical gemcitabine
is showing promising activity while taxane formulations lag a bit behind. The prospect for combined or sequential chemo or chemoimmunotherapy remains enticing but underdeveloped. New
immunostimulants will continue to be sought as
alternatives to BCG. Further out on the horizon
are more novel approaches including gene therapy, active cell-based immune therapy, and signal
targeting small molecule drugs.
All reports published thus far confirm the low systemic absorption of gemcitabine, the good tolerability with minimal local and systemic toxicity, and,
more importantly, its efficacy as an intravesical
agent, even in heavily pretreated patients. This agent
warrants further investigation in a large cohort of
patients, especially to determine the long-term durability.
Another potential chemotherapeutic drug that is still
in the intravesical formulation and testing stage is
paclitaxel. Its high lipid solubility creates logistic
difficulties for efficient intravesical delivery. However, use of dimethyl sulfoxide or bio-adhesive polymer microspheres may circumvent this difficulty
[137,138]. In vitro experiments have confirmed that
even a brief 2-hour exposure of bladder cancer cells
has significant anti-cancer potency [139].
d) New Immunostimulants
While BCG retains its role as the most effective
intravesical agent, the liability of a live organism
capable of causing a life-threatening septic infection
has encouraged a search for equally effective but less
toxic alternatives. The most well-developed new
immunostimulant on the horizon is Mycobacterial
Cell Wall-DNA Extract (MCC). Prepared from
Mycobacterium phlei, the compound contains a mixture of immunostimulatory mycobacterial DNA
attached to antigenic cell wall. In the recently
released phase 2 trial results, either a 4 mg or 8 mg
weekly dose for 6 weeks was well-tolerated with a
complete response rate in patients with CIS +/- T1G3
tumors of between 27% and 38% at 12 months
[140]. Further trials are in preparation.
e) The Farther Frontier
Efforts to develop gene therapy approaches remain at
the early stages, though proof-of-principle has been
established in animal models and limited phase 1
210
RECOMMENDATIONS
I. DIAGNOSIS AND STAGING
5. WHAT ARE
FACTORS?
1. TECHNIQUE OF RESECTION
THE
IMPORTANT PROGNOSTIC
1. Though no factor can accurately predict which
patients will have recurrence or progression of
urothelial carcinoma, the presence of higher
grade lesions, multiple and larger lesions, concomitant CIS, and prostatic urothelial carcinoma all
may increase the risk (Grade C).
1. A thorough endoscopic evaluation of patients with
documented or suspected bladder cancer should
be performed at the time of TURBT (Grade C).
2. A standardized diagram should be used to document individual tumors and biopsy sites as well
as findings of the examination under anesthesia
(Grade C).
2. A number of biological molecular markers may be
useful as prognostic factors for T1 bladder cancer
(Grade C).
3. Resection should result in the presence of muscle
in the specimen for adequate staging (Grade C).
6. UPPER TRACT, PROSTATIC, AND URETHRAL
INVOLVEMENT
4. The use of continuous flow resectoscopes should
be further evaluated and may provide advantages
(Grade C).
1. Periodic lifelong observation of the upper urinary
tract and prostate should be performed in all
patients with CIS, high grade (G3) superficial
urothelial carcinoma, or intravesical chemotherapy failure (Grade C).
5. The use of video endoscopy should be further evaluated and may provide advantages (Grade C).
6. All visible tumors should be completely resected
(Grade C).
2. Examination of the upper urinary tract and prostate is recommended in follow-up of all patients
with superficial bladder cancer with persistently
positive urine cytology in the absence of a bladder tumor (Grade C).
2. ROLE OF RANDOM AND DIRECTED BIOPSIES
1. Multiple random biopsies of normal-appearing
urothelium should not be taken in patients who
undergo TUR for low-risk superficial bladder
cancer (primary small, single or recurrent single
tumors) (Grade C).
3. Radical therapy at an early stage for patients with
relapse in the upper urinary tract or prostate may
result in a better prognosis (Grade C).
2. Multiple random biopsies of normal-appearing
urothelium are always indicated in high-risk
tumors (high grade T1, multiple tumors, recurrent
multiple tumors, or CIS) (Grade C).
II. TREATMENT
1. ROLE OF IMMEDIATE ADJUVANT INTRAVESICAL THERAPY
3. The role of multiple random biopsies of normalappearing urothelium in intermediate-risk tumors
remains controversial (Grade C).
• A single dose of chemotherapy should be given at
the time of TURBT (ideally within 6 hours but no
more than 24 hours) whether or not additional
therapy is planned, as long as no bladder perforation has occurred (Grade A).
3. ROLE OF SECOND RESECTION
1. A second TURBT should be performed in all
patients with a high grade Ta lesion or any T1
lesion (Grade B).
2. INITIAL BLADDER-SPARING APPROACH VERSUS CYSTECTOMY
2. The suggested optimal timing of repeat TURBT is
within 1 to 4 weeks after the first resection
(Grade C).
1. Cystectomy and intravesical BCG therapy are
both acceptable primary therapies for high grade
T1 disease and both options should be discussed.
Patients need to be made aware of the lifetime
risks of recurrence and progression of their
tumors as well as the morbidity, mortality, and
expected survival with cystectomy (Grade C).
4. SUBSTAGING OF T1 PATHOLOGY
• Pathologists are not agreed on the validity and utility of substaging T1 tumors by the depth of invasion in the lamina propria. This stratification of
T1 tumors cannot yet be supported (Grade C).
2. Initial bladder conservation for T1 disease with
intravesical therapy should not be initiated
211
without excluding muscle invasion by performing a repeat TURBT (Grade C).
3. An ideal candidate for conservative treatment of
T1 bladder cancer would be one with solitary or
at least completely resectable tumor, a negative
upper tract evaluation, and no evidence of invasive disease in the prostatic urethra (Grade D). Initial intravesical BCG therapy should be considered for patients with completely resected primary
and recurrent T1 tumors based on a negative reresection who can tolerate BCG and are satisfied
with their bladder function (Grade C).
4. Patients with recurrent T1 tumors should be considered for cystectomy if they have had 2 prior
induction cycles of BCG (Grade D).
3. OPTIMAL BCG ADMINISTRATION
1. Primary intravesical therapy should be induction
BCG immunotherapy with 6 weekly instillations
beginning no sooner than 2 weeks after tumor
resection (Grade B).
2. Cystoscopy with urinary cytology and possible
biopsy should be done at 3 months to confirm the
absence of recurrence or progression (Grade C).
3. Maintenance therapy should be given. (Grade A)
While comparison studies have not been done,
the SWOG regimen of 3 weekly instillations at 3,
6, and every 6 months for 3 years is recommended (Grade A) .
4. BCG FAILURE
1. Patients failing BCG should ideally be subclassified into definable groups such as BCG-refractory, BCG-resistant, BCG-relapsing, and BCGintolerant (Grade D).
2. Patients failing induction BCG therapy who recur
with high grade disease at 6 months should be
offered cystectomy (Grade C).
3. For patients failing initial induction BCG therapy
who are unfit, refuse cystectomy, or have low or
intermediate grade disease, an additional course
of a BCG-containing intravesical therapy is the
preferred option (Grade C).
4. Cystectomy is indicated if salvage therapy fails
and it should be performed in a timely manner
(Grade C).
5. NEW TREATMENT APPROACHES
HORIZON
ON THE
• Further study of therapies for failure of intravesical
therapy is to be encouraged (Grade D).
212
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Bittard H. The predictive value of muscularis mucosae invasion
and p53 over expression on progression of stage T1 bladder carcinoma. J Urol. Jan 2001;165(1):42-46; discussion 46.
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217
218
Committee 6
Muscle-invasive Urothelial Carcinoma
of the Bladder
Chair
S. B. MALKOWICZ (USA)
Members
H. VAN POPPEL (BELGIUM)
G. MICKISCH (GERMANY)
V. PANSADORO (ITALY)
J. THÜROFF (GERMANY)
M. SOLOWAY (USA)
S. CHANG (USA)
M. BENSON (USA)
I. FUKUI (JAPAN)
219
CONTENTS
1. PREOPERATIVE STAGING
III. OTHER THERAPIES FOR
MUSCLE-INVASIVE BLADDER
CANCER
2. TIMING OF CYSTECTOMY
1. THE ROLE OF PARTIAL CYSTECTOMY
3. PREOPERATIVE ASSESSMENT AND CLINICAL
CARE PATHWAYS
2. RADICAL TUR - INDICATIONS AND RESULTS
I. INITIAL CONSIDERATIONS
3. LAPAROSCOPIC AND ROBOTIC SURGERY
4. MOLECULAR MARKERS
4. BLADDER-SPARING THERAPY
II. RADICAL CYSTECTOMY
RECOMMENDATIONS
1. GENERAL OUTCOMES
2. PROCEDURAL STANDARDIZATION
3. LYMPH NODE STATUS
LYMPHADENECTOMY
AND THE
REFERENCES
ROLE
OF
4. URETERAL MARGINS AT CYSTECTOMY: DO
FROZEN SECTIONS MATTER?
5. NERVE- AND SEMINAL-SPARING
CYSTECTOMY
6. RADICAL CYSTECTOMY IN FEMALES
7. POSTOPERATIVE FOLLOW-UP: WHAT IS THE
APPROPRIATE FOLLOW-UP FOR PATIENTS
TREATED FOR MUSCLE-INVASIVE BLADDER
CANCER?
220
Muscle-invasive Urothelial Carcinoma
of the Bladder
S. B. MALKOWICZ
H. VAN POPPEL, G. MICKISCH, V. PANSADORO, J. THÜROFF, M. SOLOWAY,
S. CHANG, M. BENSON, I. FUKUI
Urothelial (transitional cell) carcinoma of the bladder is a significant neoplasm with over 55,000 new
cases and 12,000 cancer-related deaths per year in
the United States. It is the 5th most common cancer
in the USA and the 4th leading cause of cancer
deaths. The majority of these deaths are due to the
effects of muscle-invasive disease, which account
for approximately one-third of the de novo cases and
are derived from about 10% to 15% of preexisting
cases of superficial disease. The disease occurs predominantly in men yet is increasing in incidence in
women in a manner that cannot be entirely explained
by increased tobacco use [1].
I. INITIAL CONSIDERATIONS
1. PREOPERATIVE STAGING
Preoperative evaluation is based on the natural history of bladder cancer metastases and the operational
characteristics of the tests employed. Generally an
evaluation of the chest (chest x-ray or chest CT) is
performed as well as abdominal and pelvic crosssectional imaging. Both modalities suffer from errors
of understaging and overstaging in approximately
30% of patients. In one series of 105 patients, the
false negative rate with regard to positive nodes was
68% while the false positive rate was 16% [4]. MR
imaging is considered somewhat more accurate yet
still ranges from 50% to 90%. Cross-sectional imaging also provides information on urinary tract
obstruction that is clinically useful [5]. MR upstaging from T2 to T3 disease also provides independent
clinically useful information in the outcome of
patients treated by radiotherapy [6]. Bone scans may
be useful for those with signs or symptoms of bone
involvement but add little to the overall management
of patients [7]. Positron emission tomography has
had a limited role in bladder cancer staging and
diagnosis due to the excretion of tracer into the bladder. Lymph node staging has an accuracy of 80%,
which equals or exceeds other modalities [8]. In
addition, FDG and 11C-methionine PET have been
studied in the bladder.
The principal clinical findings of muscle-invasive
disease are gross or microscopic hematuria, and, to a
much lesser extent, voiding dysfunction or pelvic
pain. The diagnosis is made by transurethral resection of the lesion with the intent to obtain deep biopsies with representative samples of detrusor muscle.
Preoperative staging has classically been very inaccurate and has not improved appreciably in the past
several years. This is of particular concern when
deciding on less aggressive forms of therapy for
muscle-invasive disease. In an evaluation of SEER
(Surveillance, Epidemiology and End Results) registries, 154 patients diagnosed in 1995 were
reviewed with regard to treatment choices [2].
Patients were most commonly treated with
transurethral resection only (49.1%) or cystectomy
only (31%). In an evaluation of SEER data from
1988 to 1999, the treatment choice in octogenarians
was full or partial cystectomy in 12% of cases while
TUR alone was used in 79% of patients, despite the
fact that cystectomy is associated with the greatest
risk reduction in cancer death or death from other
causes [3].
2. TIMING OF CYSTECTOMY
The appropriate timing of cystectomy after diagnosis
has only recently been investigated. In several retrospective reviews, very similar conclusions have been
drawn. A cohort of 167 patients, 50 of whom
received no adjuvant therapy, were evaluated with
221
respect to treatment from time of diagnosis [9].
Those treated within 3 months demonstrated superior recurrence-free, cause-specific, and overall survival to those who were treated later. Final pathology in each group was similar, though a greater degree
of vascular involvement was noted in the late group.
In a series of 247 patients with a mean age of 66,
overall 3-year survival was 59.1%, with a lower survival (35%) in those with a treatment delay of 12
weeks or more compared to those treated earlier
(62.1%) [10]. Similarly, extravesical or node-positive disease was greater in those patients treated later
(84% vs. 42%). When adjusted for nodal status and
pathologic stages, the interval to treatment was still
statistically significant (HR 1.93, 95% CI [0.99 to
3.76], P = 0.05). Patient delay (second opinions) and
medical optimization were the most common reasons for delay. In a similar series of 153 cystectomy
patients, a significant increase in pT3 pathologic
stage was noted (81% vs. 52%) in the patients treated 90 days beyond diagnosis [11].
series, the index was evaluated in a general cystectomy population and was not age-specific.
Once the decision has been made to proceed with
surgery, the patient must be optimized mentally,
physically, and socially. Due to internal and external
pressures, collaborative clinical care pathways have
been increasingly used to aid in this process. Pooling
the expertise of surgeon and ancillary staff, these
guidelines attempt to safely streamline care while
heeding to increasing financial pressures. This has
been supported by studies examining radical prostatectomy [20-22]. For more complex operations, such
as radical cystectomy, more variability in the duration of hospitalization can be anticipated, but recent
studies have verified the efficacy of such guidelines
[23]. There is a financial value of a clinical care
pathway model that shortens hospitalization. Importantly, however, pathways only provide a framework
and must continue to evolve to improve patient care.
An example of a successful pathway used at Vanderbilt University is outlined: extensive preoperative
teaching as well as counseling and optimal stoma site
marking by an enterostomal nurse; early morning
hospital admission following a preoperative clear
liquid diet and bowel preparation completed at
home; limited laboratory analysis; short term or no
nasogastric tube decompression; early ambulation;
continued perioperative teaching; and post-hospitalization nursing care. These guidelines outline routine
care but, depending upon the clinical situation, deviations from the pathway can and must occur at any
time for individual patients [23].
3. PREOPERATIVE ASSESSMENT AND CLINICAL
CARE PATHWAYS
The intense surgical aspects of radical cystectomy
suggest concern for the routine use of this procedure
in elderly patients. Several clinical series, however,
demonstrate the ability to successfully perform this
procedure with good outcomes in older patients
(defined as 75 years old or older) with significant
comorbidity. The surgical mortality of such series
ranges from 0% to 4.5%, with the majority less than
2% [12-16]. The patients have been classified
according to the American Society of Anesthesiologists rating. Even those series with patients scoring 3
or higher have demonstrated 0% mortality [13]. Less
data is available with regard to long-term follow-up
in elderly patients. In a recent report on 38 elder
patients (mean age 79) with 22 months of follow-up,
29% of patients were alive. In the 17 patients in
whom the cause of death could be established, 14
were due to bladder cancer [17]. In another series of
96 elderly surgery patients, the perioperative mortality was 3.1% and all-cause mortality at 3 months was
8.3% [18].
This pathway is safe and effective. The overall minor
complication rate was approximately 30% with a
major complication rate of 5% and mortality rate of
1%. Of these minor complications, postoperative
paralytic ileus was the most common (57%). The
median duration of hospital stay was 7 days [23].
Other series have had similar results [14].
Despite streamlining and decreasing hospitalization,
the clinical outcomes do not differ greatly from past
series. The overall complication rate from the Duke
University cohort was 32% and operative mortality
was 2.5% [24]. Figueroa et al. reported an early complication rate of 25% in patients less than 70 years of
age and 32% in patients 70 years of age or older [14].
Montie and Wood reviewed complications over an 8year period in the 1980’s and reported an operative
mortality rate of 0.4%. Their “technical complication” rate was 2% but minor complications were not
specifically discussed [25]. The vast majority of
The impact of comorbid disease on patients undergoing cystectomy in general was evaluated in a
cohort of 106 patients (mean age 65) using the
Charlston Index. This index score of comorbidity
was associated with overall survival, disease-specific survival, and risk of extravesical disease depending on the specific outcome model tested [19]. In this
222
patients (85%) underwent ileal conduit diversion.
This was also the case in a recent series from Great
Britain where 93% of patients underwent an ileal
loop diversion. The overall “adverse event” rate was
22% with sepsis being the most common, followed
by thromboembolic complications including deep
venous thromboses and pulmonary emboli. Their
overall mortality rate was 1.9% [26].
A retrospective evaluation of the retinoblastoma
gene product pRb demonstrated worse clinical outcomes such as 5-year survival (33% vs. 66%) in
those patients with absent or elevated expression of
protein. Further stratification was obtained when a
model evaluating p53 and pRb was evaluated (79%
vs. 16% 5-year survival) [31]. The evaluation of
angiogenesis-related predictors such as thrombospondin has the ability to predict patient outcomes
yet are not independent of p53 [32].
A clinical pathway can be used safely with different
types of diversion. No significant difference in hospital stay among orthotopic neobladder patients
compared to those patients that undergo ileal conduit
has been demonstrated [27]. Many factors influence
the choice of diversion and how patients recover, but
diversion type did not correlate with hospitalization.
Benson et al. reported on outcomes comparison in 73
patients who underwent radical cystectomy and
either conduit or continent diversions and also found
no significant difference in either complication rate
or length of hospitalization between urinary diversion types [28].
The exploration of several putative markers in moderate size cohorts of cystectomy patients has yielded
a group of candidate markers with independent predictive ability for lymph node involvement and clinical progression in patients with muscle-invasive disease [33-40]. The majority of these, such as transforming growth factor-beta, soluble E-cadherin, and
uroplasminogen/uroplasminogen receptor can be
measured in the serum. If confirmed prospectively,
these markers, alone or in combination, may provide
further guidance for performing more extensive
lymph node dissections or considering the use of
adjuvant therapies beyond surgery. In one multifactorial evaluation of several cell cycle markers (p53,
p21, pRb, and p16) altered expression was noted in
each marker, yet p53 demonstrated the most robust
predictive power, followed by p21 [41].
4. MOLECULAR MARKERS
The ability to provide stratifying criteria beyond
tumor stage and lymph node status to the clinical
characterization of muscle-invasive tumors would be
extremely useful. Preoperative markers may predict
the greater probability of lymph node involvement or
tumor recurrence, and tissue markers might further
direct the application of adjuvant therapy or alter the
intensity of postoperative follow-up. Furthermore,
there is the possibility of optimally identifying
patients best suited for a particular initial therapy.
Currently several fairly large retrospective studies of
archival material have demonstrated the potential
utility of several classic markers, and many smaller
studies are suggesting the utility of other identified
candidate biomarkers.
Less data on markers exists for those patients treated
with bladder-sparing protocols. In 1 evaluation of 82
patients, p53 and p21 status had independent predictive power in determining outcomes and survival in
those patients treated with combined modality
approaches. pRb offered little information [42]. However, in another study of 108 patients, loss of pRb
staining provided the strongest predictor of a complete
response to therapy and relapse-free survival [43].
Currently, 2 large prospective randomized trials are
ongoing to evaluate the ability of p53 status to guide
therapeutic decisions. The multi-institutional p53
trial is investigating the role of p53 status as it pertains to adjuvant chemotherapy in organ-confined
disease. Those patients who are p53-positive will be
randomized to observation or 3 courses of adjuvant
MVAC. The study is designed to detect a 20% difference in survival. In another study at Memorial
Sloan Kettering Cancer Center, patients with clinically organ-confined disease and wild-type p53
staining will undergo complete TUR and neoadjuvant MVAC followed with conservative management. In addition to feasibility, the study will evaluate how many patients can be appropriately treated
with bladder-sparing therapy.
A retrospective review of 243 cystectomy specimens
has identified abnormal p53 expression as an independent marker for disease progression (60%-80%
vs. 7%-11%) and disease-specific mortality in organconfined muscle-invasive disease [29]. A further
evaluation of p21 waf1/cip1, a cyclin dependent
kinase inhibitor, and p53 in 242 cystectomy specimens demonstrated the independent predictive ability of p21 status with respect to tumor progression
and patient survival. It was also evident that preservation of p21 function had a positive impact on p53positive tumors, with poorest outcomes demonstrated in those cases with aberrant expression for both
markers [30].
223
In a series of 1026 cases from Mansoura, overall 5year survival was 48% [49]. This series is notable for
the difference in pathologic case mix since 59% were
squamous cell carcinoma and only 22% urothelial
(transitional cell) carcinoma. Positive lymph nodes
were found in 18.3% of cases and demonstrated a
23.4% 5-year survival. Five-year survival was
approximately 60% for pT2 disease, 45% for pT3,
and 16% for pT4.
Surgical mortality rates in most series range from 1%
to 3%. Significant preoperative cardiovascular morbidity, the intensity of the surgery, and potential septic complications associated with cystectomy and
urinary diversion contribute to this. Contemporary
series also demonstrate that 25% to 30% of patients
will experience morbidity associated with the
surgery within the first 4 months, attesting to the
intensity of the surgery. Blood loss during cystectomy can range from 600 to 1800 mL with some significant outliers. Newer stapling and cautery devices
may help decrease this particular morbidity. In a
prospective trial of 70 patients, an articulating linear
staple cutter was compared to traditional techniques
and demonstrated significantly lower blood loss and
less need for transfusion (5.7% vs. 34.3%) (Level 2,
[50]). These devices may be particularly useful in
women, in whom an association with greater blood
loss and transfusion requirement has been documented in some series [51].
Classically, the outcomes for salvage cystectomy
have been significantly worse than those encountered in nonirradiated patients. In a small series of
patients (18), it was demonstrated that this surgery is
feasible even with continent diversion [52]. Average
blood loss was 840 mL but continence rates were
67% during the daytime and 56% at night. In another series of salvage cystectomies in patients originally treated for prostate cancer, an average blood loss
of 1175 mL was noted with an early complication
rate of 55% [53]. No rectal injuries or perioperative
deaths occurred, and extravesical disease was more
common (60% vs. 30%) in those patients who underwent prior radiation therapy. In expert hands, surgery
even in the presence of gross nodal disease can be
warranted. In a series of 84 patients, a 24% 10-year
survival was noted [54].
Surgery also can play a role in the resection of local
or distant metastases in carefully selected patients
[55-57]. With preoperative chemotherapy, 40% to
50% of locoregional resected lesions will demonstrate no tumor, while distant sites may be positive in
up to 80% of cases. Overall median 5-year survival
is approximately 33% to 46%.
II. RADICAL CYSTECTOMY
1. GENERAL OUTCOMES
Intermediate and long-term results from radical cystectomy are available from several series and provide
a benchmark for alternative forms of treatment. In
the USC series of 1054 patients, median follow-up
was 10.2 years with a range of 0 to 28 years for
patients with a median age of 66 (22-93) [44] . Overall recurrence-free survival was 68% and 66% at 5
and 10 years. In patients with superficial (pT0-pT1),
node-negative disease, 5- and 10-year survival was
clustered at 92% to 83% and 86% to 78%. For muscle-invasive, organ-confined disease, 5- and 10-year
findings were in the 89% to 76% range, while
extravesical, node-negative tumors demonstrated a
62% 5- and 10-year survival with pT4 tumors
exhibiting a 50% to 45% survival over this time period. Those patients with positive lymph nodes (24%)
demonstrated 5- and 10-year survivals of 35% and
34%, respectively. Thirty percent of patients demonstrated recurrences at a median time of 12 months,
with a local recurrence rate of 7%.
In a recent evaluation of 300 patients from Memorial Sloan Kettering Cancer Center with a median follow-up of 65 months, the disease-specific survival
was 67% and there was clearly a dichotomy between
organ-contained and non-organ-contained disease
(60%-63% for pT2a-pT2b and 31% for pT3-pT4)
[45]. In this regard, the distinctions between pT3a
and pT3b disease have been evaluated in one series
demonstrating no difference in the survival rate,
lymph node status, or recurrence rate among these
patients [46].
In a pooled series of 518 patients with a median follow-up of 4.4 years, the overall survival rate was
58% and the 5-year node-negative survivals for T1 to
T4 disease were 81%, 74%, 47%, and 38% respectively [47]. Node-positive patients demonstrated a 5year survival of 30%.
A contemporary series of 507 patients (median age
66) demonstrates a 5-year disease-free and overall
survival of 73% and 62% in patients with organ-confined, node-negative disease and 56% and 49% for
extravesical, node-negative cases [48]. Positive
lymph nodes were found in 24% of patients. Local
recurrence ranged from 3% to 11% depending on
tumor stage. Distant metastases were noted in 25%
of patients with localized disease and 51% of
patients with positive lymph nodes.
224
2. PROCEDURAL STANDARDIZATION
trast agents demonstrating improved staging in
prostate cancer patients may prove valuable in further discrimination of lymph node status in patients
with bladder cancer [62]. Current positron emission
tomography techniques are not useful, with a reported false negative rate of approximately 30%.
Further efforts have been made to standardize the
basic aspects of cystectomy to provide uniformity in
outcomes. In an evaluation of 637 patients from a
single institution, it was demonstrated that improved
overall survival rate and a reduced local recurrence
rate were associated with negative surgical margins
and a greater number of lymph nodes removed [58].
Survival was improved if 13 or more nodes were
sampled, and there was a greater correlation with
negative soft tissue margins in node-negative and
node-positive patients if 13 nodes were sampled.
This concept was further evaluated in a cooperative
group effort in which 1091 cystectomies from 4
institutions (16 surgeons) were evaluated [59]. Surgical margins were correlated with patient age, prior
therapy, tumor stage, and the extent of the lymph
node dissection. General recommendations included
an effort to examine 10 to 14 nodes per case and
strive for a positive margin rate of less than 10% in
nonbulky tumors, less than 15% in pT3 to pT4
lesions, and 20% in salvage situations. Reasons for
limiting the lymph node dissection included age
greater than 75 (in 35% of cases) and significant
prior treatment (50%). Higher volume surgeons
tended to operate on more elderly, sicker, and pretreated patients. In another evaluation of patients
participating in a cooperative group trial for neoadjuvant chemotherapy, it was noted that the overall
quality of pathological examination was high, but in
10% of specimens no mention of the soft tissue margins was made, nor were lymph nodes described in
18% of cases [60]. In a secondary analysis of this
patient group (SWOG 8710), a multivariable model
looking at 5-year survival and local recurrence (overall 54% and 15%) in this group of 268 patients
demonstrated that negative surgical margins (hazard
ratio [HR] 0.37, P = 0.0007) and the effect of 10 or
greater nodes removed (HR 0.51, P = 0.0001) had an
impact independent of MVAC therapy, node status,
or pathologic stage [61]. These data strongly suggest
the impact of surgical factors on the outcome in cystectomy patients and the value of suggesting general
standards for the procedure.
3. LYMPH NODE STATUS
LYMPHADENECTOMY
AND THE
ROLE
Sentinel lymph node evaluation has become standard
in certain malignancies and is being evaluated in
muscle-invasive bladder cancer. This is somewhat
complicated in the case of muscle-invasive bladder
cancer since the lymphatic drainage of the bladder is
variable and there is minimal data correlating tumor
position in the bladder with positive lymph node
location. Additionally, there is inferential data suggesting the phenomenon of skip metastases to higher
echelon nodes as well as crossing lymphatic drainage
[63-65]. Current studies employing endoscopic tracer instillation prior to cystectomy demonstrate the
absence of a sentinel node at the time of cystectomy
in up to 20% of cases, and the localization of sentinel
nodes, when detected, beyond the obturator node
region in a third of the cases. This is clearly an area
for further study that may provide clinically useful
information.
a) Clinical Practice
The value of a lymph node dissection in conjunction
with radical cystectomy with regard to obtaining
more accurate pathologic assessment and potentially
improved survival has been advocated by several
academic groups for many years. Recent clinical
data can provide a better assessment of the validity
of these claims with regard to survival and optimal
stratification of patients undergoing surgical treatment for muscle-invasive disease. Both clinical stage
and lymph node status independently contribute to
predicting prognosis, but the correlation of nodal
metastasis and increased clinical stage is clear.
Current general practice suggests that less than half
of American patients undergoing cystectomy do not
undergo pelvic lymph node dissection or have 4 or
less nodes removed. In those patients with lower
stage clinical disease, 1 percent or less underwent a
lymph node dissection in conjunction with their
surgery [66]. Therefore, a disparity exists between
general practice and professional recommendations
for this procedure in patients undergoing cystectomy.
OF
Clinical staging of lymph node status in patients with
muscle-invasive disease remains inaccurate. The
finding of clinically occult disease can range from
15% to 27% with cross-sectional imaging using MRI
and computed tomography. New ferromagnetic con-
The standard pelvic lymph node dissection includes
the obturator packets and extends laterally to the
external iliac vein. The cephalad extent of the dissection terminates at the bifurcation of the common
iliac vessels. An extended version of the procedure
225
Summary
demarcates the inferior mesenteric artery as the
cephalad boundary and includes paracaval, intra-aortocaval, para-aortic, presacral, common iliac, and
external iliac nodes as part of the dissection.
The value of extended lymph node dissection as
noted by recent findings in the literature is not yet
reflected in general urologic practice. This gap
needs to be bridged as there appears to be some
curative value in the lymph node dissection alone
and potential greater value in identifying high-risk
patients with low-volume disease with the greatest
potential for cure with adjuvant therapy. Lymphatic anatomy of the urinary bladder requires further
investigation with respect to sentinel node status,
skip lesions, and crossover drainage. Additionally,
the value of lymph node density as a predictive
index needs further validation. The development
of molecular markers for the prediction of nodal
status and prediction of clinical prognosis in nodepositive patients will further expand our ability to
stratify and optimally treat this patient population.
b) Impact on Survival
Since 15% to 25% of patients with clinically nodenegative disease may harbor micrometastases, some
patients will definitely benefit from a lymph node
dissection. Classically, lymph node involvement was
almost uniformly fatal, yet the incorporation of
lymph node dissection in patients with gross
adenopathy, microscopic disease, and no pathologic
lymph node disease provides a survival advantage.
In 84 patients with cystectomy and lymph node dissection alone in the setting of evident positive disease, the 10-year survival rate was 24% [54]. In general, 5-year survival is 25% to 35% in patients with
positive nodes. This figure is even higher (44%) in
those patients with node-positive organ-confined disease. In comparing node-negative patients with a
standard or extensive dissection, a slight survival
advantage has been described in those patients
undergoing the extended dissection [67].
4. URETERAL MARGINS AT CYSTECTOMY: DO
FROZEN SECTIONS MATTER?
The role of frozen section pathology of the ureteral
margins at the time of cystectomy has been controversial. Although a common practice, little evidence
has been presented either way for the impact on outcomes with this practice. The persistence of tumor on
successive biopsies could result in excessive ureteral
shortening and the need to modify the urinary diversion. Furthermore, the concern for local recurrence
or an increase in ureteral anastomotic strictures has
persisted. The available data on the impact of ureteral margins [76-80] suggest a 2% to 8% chance of
detecting carcinoma in situ on frozen section during
cystectomy. Some form of ureteral abnormality in
the form of atypia or dysplasia may exist at twice
that rate. In 4 clinical series with a median follow-up
of 50 months, 1 of 51 patients with persistent abnormal findings on repeat frozen sections developed an
anastomotic recurrence and 4 other patients developed upper tract recurrence over a mean follow-up of
42 months [76,79]. In one series, all 4 patients with
CIS at the margin eventually died of their disease,
yet none had an upper tract recurrence [77].
Recent studies have been evaluating the factors
which predict for survival advantage with a lymph
node dissection. There are data for and against the
predictive value of the classic TNM system [68,69].
Newer reports suggest the value of the total number
of nodes harvested in a dissection [70-73]. Recently,
there is no agreed upon optimal number required to
confer a survival advantage. More recently, it has
been suggested that normalization of the lymph
involvement by creating a ratio of the positive nodes
to the number of dissected nodes may provide superior clinical information. A cutpoint of less than or
greater than 20% node positivity was first suggested
as a discriminator of survival in such patients and
similar findings have been noted in other series [68].
A recent multicenter retrospective evaluation
demonstrated the independent prognostic value of
node density and the total number of positive nodes
in predicting progression and survival (AUA 2004).
It has also been recently demonstrated that more
nodes are demonstrated on final pathology when the
material is sent in distinct anatomic packets rather
than as an en bloc specimen [74].
5. NERVE- AND SEMINAL-SPARING
CYSTECTOMY
Further data from the SEER database demonstrate
the impact of the extent of surgery on survival [75].
While the John Hopkins group pioneered potencysparing cystoprostatectomy, potency cannot be
achieved in a large percent of patients. Even when
the operation is performed by skilled and experi-
226
enced surgeons, the preservation of normal sexual
function does not exceed 40% to 60% of cases and
urinary incontinence, mainly during the night, persists in a significant number (Level 3, [81]). Thus,
modified cystectomy has been tried, with preservation of vas deferens, prostatic capsule (hypertrophied
transition zone is removed with bladder), or prostate
and seminal vesicles in males, and all internal genitalia in females. An ileal bladder substitution is anastomosed to the margins of the prostate in males and
urethra in females. Selection of patients should be
limited to lower clinical stage patients since prostatic involvement is associated with significant clinical
progression and seminal vesicle involvement, while
rare (less than 1% of most large cystectomy series),
is associated with a less than 10% 3- and 5-year survival [82,83].
malities in females. After the operation, erections
were normal in 7 men, with antegrade ejaculation in
5, and vaginal lubrication was reported to be normal
in all women. Daytime continence was achieved in 9
men and 2 women, while nighttime continence was
achieved in 7 and 2, respectively. One woman and 3
men perform intermittent catheterization because of
postvoid residual urine. At a mean follow-up of 3.5
years, 2 patients have died of distant metastasis
without local recurrence and 1 developed prostate
cancer 5 years after cystectomy.
Vallancien et al. (Level 3, [87]) reported treatment
results of seminal-sparing cystectomy performed in
100 male patients (mean age 64) including 40 pT2,
23 pT3, and 13 N+ patients. All patients had a normal digital rectal examination, PSA less than 4
ng/mL, and no hypoechoic areas of the prostate. In
the vast majority of the patients, cystectomy was carried out just after TURP. The 5-year cancer-specific
survival was 90% in pT0 to pT1, 73% in pT2, 63%
in pT3, and 8% in N+. Prostate cancer was diagnosed
in 3 patients. At 1 year follow-up, 86 of 88 patients
are fully continent during the day and 84 (95%) void
1 to 2 times a night to stay dry. Of 61 patients with
previously adequate sexual function, 50 (82%) maintained potency with retrograde ejaculation secondary
to TURP, 6 have partial potency, and 5 are impotent.
Muto and Moroni started this modified cystectomy,
which they call “seminal-sparing cystectomy,” with
orthotopic bladder replacement in the treatment of
superficial bladder cancer refractory to conservative
management in a cohort of patients with normal sexual activity who wished to preserve it and no tumor
involvement in the prostatic urethra [84]. Subsequent
to their preliminary report on 42 patients in 1998,
Muto et al. reported long-term follow-up (median of
68 months) results in 61 evaluable male patients
(mean age 49) including 5 with invasive (T2G3)
bladder cancer, all of whom preoperatively had a
normal serum PSA level (0.8-3.4) and transrectal
ultrasound of the prostate (Level 3, [85]). Normal
erectile function without pharmacologic help was
preserved in 95% of the patients. Complete daytime
continence was reached in 95% and nighttime continence was reached in 31% of the patients. The early
postoperative and delayed complication rate was
18% and 26%, respectively. Although prostate cancer and high grade prostatic intraepithelial neoplasia
were noted in 1 and 3 patients, respectively, these
patients had undetectable (<0.2 ng/mL) PSA levels
without adjuvant therapy at a median follow-up of 19
months. Fifty-five patients are alive and 6 patients
are dead, 5 of cancer progression.
A small series of men by Fang-Jian et al. [88] demonstrated preservation of sexual function in 75% of men
who were intact preoperatively, while a series of 25
men reported by Saidi et al. [89] with a median follow-up of 46 months (ages 47-75) did demonstrate
one case of prostate cancer after 36 months, which
was successfully treated with radiation therapy.
Colombo et al. (Level 3, [90]) studied 27 male
patients (mean age 52) with superficial high-risk (22
patients) or muscle-invasive T2 bladder cancer (5
patients) who underwent nerve- and seminal-sparing
cystectomy with construction of neobladder following sextant prostatic biopsy and transurethral resection of the prostate. Fully normal postoperative erectile function was documented in all patients and a
retrograde ejaculation with reliable sperm retrieval
from urine was also documented. Further, diurnal
and nocturnal urinary continence was achieved
immediately after indwelling catheter removal in 18
(67%), while the remaining 9 patients obtained complete urinary continence within 15 days after catheter
removal. No patients needed to wear any pads. At a
mean follow-up of 32 months, no patient had local
recurrence or prostatic carcinoma. One patient with
positive lymph nodes died of disseminated disease.
Horenblas et al. (Level 3, [86]) applied this procedure in 10 males and 3 females with bladder cancer
clinically staged T1 to T3 (mean age 55). All patients
with tumor growth in the bladder neck, males with
tumor in the prostatic urethra, and females with invasive tumor in the trigone were excluded from the
surgery. Further requirements are patient motivation
for the preservation of sexual function, no prostate
cancer in males, and no cervical or uterine abnor-
227
Summary
developed to the level of the bladder neck, and the
anterior and posterior dissections are connected with
preservation of the bladder neck.
Seminal-sparing cystectomy (preservation of
seminal vesicles, vas deferens, and prostate or
prostatic capsule) in relatively young and sexually active patients with organ-confined bladder
tumors without high risk of subsequent urethral
recurrence is effective in preservation of not only
sexual activities but also urinary continence. The
effect on therapeutic efficacy associated with this
surgical approach will require longer follow-up
studies in larger patient populations.
It was recently reported that there is a very low incidence of secondary malignancies discovered incidentally or urothelial involvement of adjacent organs
found at the time of cystectomy [99]. In this series,
only a single gynecologic malignancy was found and
involvement of the uterus by direct extension of
bladder cancer was discovered in only 2 patients,
both of whom had clinical suspicion based on bimanual examination or preoperative imaging. Thus, in
most women the risk of gynecologic involvement of
urologic malignancy is small and can usually be
determined either preoperatively or at the time of
surgery. This was also the case in another larger
series by Ali-el-Dein et al. [100]. In an evaluation of
609 female cystectomy specimens, 64% of which
were squamous cell carcinoma, gynecologic organ
involvement by the bladder cancer was seen in 2.6%
of cases. The involvement of gynecologic organs
was most commonly noted in posterior wall tumors.
The potential for improved functional outcomes and
quality of life through preservation of gynecological
organs, particularly among young women with invasive bladder cancer, is an area of ongoing research.
These younger women are more likely to be concerned about preservation of fertility and continuation of normal hormonal status [101].
6. RADICAL CYSTECTOMY IN FEMALES
In women, radical cystectomy for muscle-invasive
bladder cancer has historically been the equivalent of
an anterior exenteration. This includes removal of
the uterus, fallopian tubes, ovaries, bladder, urethra,
and a segment of anterior vaginal wall. This remains
the gold standard. However, early detection combined with a desire to improve the functional outcomes including sexual abilities and urinary control
have led surgeons to modify their techniques in
select patients where preservation of disease-free
urethra is possible.
Although the majority of women still undergo ileal
conduit urinary diversion or continent cutaneous
diversion, orthotopic urinary diversion has become
increasingly viable as an option. Stein et al. and others subsequently have demonstrated the oncologic
safety of orthotopic reconstruction in properly
selected female patients [91-93]. Exclusion criteria
for orthotopic neobladder reconstruction include
tumor involving the bladder neck, diffuse carcinoma
in situ, and a positive bladder neck margin at the time
of radical cystectomy [91]. In addition, females with
large, palpable tumors along the anterior vaginal
wall are not appropriate candidates. In properly
selected patients, local recurrence rates have been
extremely low and functional outcomes have been
comparable to those reported among male patients
[94-98].
In properly selected patients, functional outcomes
have been comparable to those reported among male
patients [92-98]. Daytime continence rates range
from between 70% to 95%, with high rates of overall satisfaction. There may be a higher rate of urinary
retention regarding intermittent catheterization, and
all patients undergoing diversion should receive preoperative counseling regarding this as well as other
possible complications. The newest techniques in
male patients can be used in the female patient. In
fact, robotic cystectomy and orthotopic diversion in
females has recently been described [93].
7. POSTOPERATIVE FOLLOW-UP: WHAT IS THE
APPROPRIATE FOLLOW-UP FOR PATIENTS
TREATED FOR MUSCLE-INVASIVE BLADDER
CANCER?
The technique and outcomes of orthotopic diversion
in females have been well-described [95,96]. These
technical refinements include avoidance of overlapping suture lines, the interposition of a vascularized
omental pedicle, and preservation of the anterior
vaginal wall [94]. In patients with nonpalpable
tumors, the plane between the posterior bladder wall
and the anterior vaginal wall can be developed while
ligating the posterior-lateral pedicles. The plane is
The majority of patients with muscle-invasive bladder cancer are treated with cystectomy and some
form of urinary diversion. After recovery they are at
risk for local and distant recurrence as well as
metabolic deterioration of their renal and gastroin-
228
testinal systems. Patients can also experience disease
recurrence in the urethra or upper urinary tract.
Those individuals treated with bladder-sparing therapies also require continued monitoring of their
intact bladder. An appropriate schema for disease
monitoring should be based on natural timing of
recurrence in patients with invasive disease and the
probability of disease recurrence or functional deterioration at particular sites. Contemporary cystectomy series demonstrate a 5% to 15% chance of local
disease recurrence that is associated with nodal status (25%-50%) at the time of surgery and clinical
stage of disease (15%-50%). The majority of recurrences are manifest in the first 24 months and many
are concentrated within 6 to 18 months after surgery.
Fifty percent to 70% of these local recurrences are
noted without concomitant distant disease.
occurs in 3% to 15% of women and is associated
with tumor at the bladder neck.
Upper tract recurrence is uncommon (2%-4%) in
cystectomy series and generally occurs 24 to 40
months after surgery. Those patients with carcinoma
in situ, urethral involvement, and ureteral involvement are at higher risk of recurrence. Ureteric
obstruction occurs in 1% to 15% of cases and is managed by open reoperation or endoscopic techniques.
Renal deterioration can occur in up to 30% of
patients over time with or without obstruction.
Appropriate follow-up of the cystectomy patient
would include frequent early monitoring of the chest,
abdomen, and pelvis for local and distant recurrence
as well as a standard metabolic evaluation. Monitoring of the upper tracts and urethra is also important.
A reasonable schema based on the available data for
site of recurrence and the time frame for recurrent
disease is offered by Bochner et al. [104].
Distant recurrence is noted in approximately 50% of
cystectomy patients and the majority (80%-90%) of
these is noted within 24 months. Some progression is
demonstrated from year 2 to 5 and even beyond 5
years. Again, nodal status and pathologic tumor stage
strongly influence the probability of recurrence. The
most common sites of recurrence are the lung, liver,
and bones.
III. OTHER THERAPIES FOR
MUSCLE-INVASIVE BLADDER
CANCER
Metabolic alterations of renal and GI function can
occur frequently in patients who have undergone a
cystectomy and urinary diversion. Vitamin B12 reabsorption and bile acid metabolism are affected by
significant resection of the distal ileum. Long-term
evaluation of patients demonstrates that 35% of
patients may require B12 supplementation after 3 to
5 years [102]. Hyperlipidemia has also been associated with long-term urinary diversion. Mild metabolic acidosis (hypochloremic, hypokalemic) is noted in
approximately 15% of patients and may require
metabolic supplementation. In some instances this
can be due to poor emptying, requiring an evaluation
for reservoir deterioration.
1. THE ROLE OF PARTIAL CYSTECTOMY
Partial cystectomy is an alternate form of therapy for
muscle-invasive disease in a select cohort of
patients. The available data is derived from retrospective reports and much of the information must be
distinguished from primary urachal lesions or
metastatic deposits to the bladder [105-108].
Approximately 5% (range 5%-15%) of any patient
group presenting with muscle-invasive disease might
be considered for partial cystectomy. The principle
limiting factor is the location of the tumor. In the
majority of cases these represent lesions of the bladder dome. In a recent clinical series, 81% of tumors
were clinical stage T2 or T3, while approximately
40% demonstrated similar stages pathologically
[109]. In general, there was a stage shift downward.
Overall 5-year survival was 69%, with 74% of these
patients maintaining an intact bladder. On univariate
analysis, carcinoma in situ and multifocal lesions
were a risk factor for superficial recurrence (80%),
while positive surgical margins and lymph node
involvement were factors for advanced recurrence
(80% of patients). Median follow-up was 33 months.
Urethral recurrence is a major concern and may
occur in 5% to 15% of patients. The relative risk of
recurrence is increased with prostate pathology and
is highest in those patients with stromal invasion of
urothelial carcinoma (20%-60%). The risk of distal
urethral recurrence is not amplified with carcinoma
in situ or tumor multifocality. It appears that the risk
of urethral recurrence is lower in those individuals
who have undergone an orthotopic diversion (2%4%) compared to those individuals with cutaneous
diversions (4%-8%) [103]. Whether this is due to
patient selection or the effect of urine in contact with
the urethra is not totally clear. Urethral recurrence
Contemporarily, it should be possible to perform
such surgery without compromise of bladder function and with an overall low complication rate. More
229
recent series demonstrate no instances of wound
implantation. Patient selection is a key component of
success (mean tumor size of the most recent series
was 3.3 cm). Those lesions in the lateral wall and
trigone are the most difficult to treat in this manner
and other techniques should be considered.
rates ranging from 40% to 60% in T2a and T2b disease, which includes therapeutic consolidation with
cystectomy [114,118]. The treatment of T2 and
greater tumors with complete TUR and chemotherapy has yielded 60% 5-year survival with bladder
preservation [119].
One indication for partial cystectomy in a site other
than the dome is for a tumor associated with a bladder diverticulum. Data for outcome assessment is
very scanty. A recent series of 39 patients treated
patients a variety of ways, including with partial cystectomy, for tumor in a diverticulum [110]. Thirteen
demonstrated T2 or greater disease and had 45% 5year survival. Those patients with Ta and T1 disease
performed better (83% and 72%).
Two major prospective reviews provide significant
information with regard to application and outcomes
of this approach. Herr reported a 10-year experience
on 99 patients treated with complete TUR and Solsona described a series of 133 patients with invasive
cancer treated in the same fashion. In both cases,
these cohorts represented approximately 21% of the
patients evaluated with muscle-invasive disease during this time period [120,121]. The 10-year diseasespecific survival in both groups was approximately
75%. In Herr’s series, those patients with residual T1
disease fared less well with a 57% survival rate.
Additionally 34% of patients experienced a muscleinvasive relapse requiring therapeutic consolidation
with cystectomy. The Solsona series demonstrated
relapse with muscle invasion in 36% of patients, a
third of whom could be salvaged with radical
surgery.
The small number of patients in these series precludes meaningful comparison to cystectomy. There
are no prospective trials of this technique compared
to cystectomy or TURBT. Overall 5-year survival
tends to be somewhat lower stage per stage than contemporary cystectomy series, yet such a comparison
involves multiple biases.
Additionally, this technique has been incorporated
into bladder-sparing protocols after initial
chemotherapy in small numbers of patients (n = 13)
[111]. Those patients consolidated to a T0 status after
partial cystectomy have a 5-year survival of approximately 60% [111,112].
The Herr series did not evaluate tumor size and morphology yet it is intimated that careful selection of
tumors was performed. A univariate and multivariate
analysis was performed with the Solsona data which
yielded only carcinoma in situ as a variable for disease progression. Large lesions were predominantly
papillary with few sessile lesions greater than 3 centimeters.
2. RADICAL TUR - INDICATIONS AND RESULTS
Classic data suggest the potential for long-term disease-free survival in select patients treated with
transurethral resection (TUR) alone of their bladder
tumor [113,114]. Advantages of this form of therapy
are decreased morbidity and greater applicability to
populations with significant comorbidity. Disadvantages include the significant potential for pathologic
misstaging and undertreatment of significant disease.
The available data suggests that transurethral resection alone is an option in a limited number (approximately 20%) of patients presenting with muscleinvasive disease. Very careful consideration to the
clinical characteristics of the tumors is essential in
selecting patients for such therapy. Close follow-up
of these patients is mandatory, with the understanding that approximately a third of these patients will
experience muscle-invasive relapse and may require
consolidation of therapy with radical cystectomy. No
data is available with regard to molecular markers
and how they may better discriminate outcome.
In efforts to obtain a “complete” TUR prior to cystectomy in a series of 90 patients, 29.4% with initial
muscle-invasive disease demonstrated pT2 tumor on
the cystectomy specimen [115]. In another series of
80 patients with a precystectomy complete TUR,
75% of the cases demonstrated residual disease, and
the T2 patients demonstrated pT2 or higher pathology in almost all cases [116].
3. LAPAROSCOPIC AND ROBOTIC SURGERY
Minimally-invasive techniques have had an impact
on all aspects of urology, and with their maturation,
case series reports are now regularly reported on
their application to invasive bladder cancer, which
has traditionally been associated with the most
In unselected classic retrospective series determined
primarily by patient preference, not physician selection, 5-year survival rates were 30% to 37%
[113,117]. Other studies demonstrate 5-year survival
230
aggressive forms of open surgery in urology. A combination of techniques have been employed to perform a cystectomy and some form of urinary diversion including pure laparoscopic cystectomy and
extracorporeal ileal loop or continent pouch, complete intracorporeal cystectomy and diversion (ileal
loop and continent diversion), and hand-assisted
laparoscopic radical cystoprostatectomy and extracorporeal urinary diversion. Use of robotic assistance for radical cystectomy has also been reported.
Approximately 150 to 200 cases have been described
in the literature.
ed is 45%-55% with disease-specific survival in the
55%-65% range. Disease-specific survival with an
intact bladder is slightly decreased in the 43%-55%
range [122-125]. Smaller series of highly selected
clinical T2 patients have demonstrated higher overall
and disease-specific outcomes (70%-80%) [126]. On
the average, 25% to 30% of patients require cystectomy as a component of treatment consolidation.
Clinical and molecular characteristics of patients
may aid in selecting appropriate candidates for therapy. Early series demonstrated the poor outcome of
patients with an initial presentation of hydronephrosis [122] and other investigators have shown the negative impact of initial carcinoma in situ [127]. In 1
series of 111 patients, 60 demonstrated a complete
response to initial chemotherapy. These were stratified by p53 expression status. All patients with T2
p53-negative tumors survived 10 years, while those
patients with T2 disease who were p53-positive
demonstrated a 47% 10-year survival [128]. The
impact of p53 status on higher clinical stage disease
was minimal (67% vs. 63%). Recent data in patients
receiving gemcitabine and radiotherapy as part of a
bladder preservation protocol suggest that overall
quality of life is not significantly impaired for overall parameters and is slightly lower in bladder-specific measurements (FACT-BL) for those patients
receiving higher doses of therapy. This reflects the
tolerability of such regimens [129].
The common denominator in these reports is previous extensive experience with laparoscopic techniques and a significant operative time (8 to 12
hours) for the initial cases. Blood loss appears generally less than that encountered with open surgery
(300 to 600 mL) while hospitalization times vary
with respect to regional and national practice. In several American series the postoperative period ranges
from 5 to 8 days.
Complications include major vascular injury and
hypercarbia necessitating open conversion. In many
series few early complications are reported. Contrasting this to early outcomes with open surgery at
centers of excellence, this suggests very careful
patient selection in these small series, a higher
threshold for defining complications, or a decrease in
overall early complications that will be sustained
with larger numbers. Currently follow-up on most
patients is quite short.
Summary
Multimodality organ-preserving therapy for invasive bladder cancer is feasible and provides reasonable results for those individuals unfit or
unwilling to undergo radical cystectomy. There
are no direct comparisons of organ-sparing protocols to radical cystectomy. Those patients with
resectable clinical T2 disease will attain the best
clinical outcomes. p53 status has been suggested
as a potential prognostic factor in determining
favorable outcomes with this mode of therapy,
and quality of life is not severely impaired by such
treatment. Multimodal organ-sparing therapy
should be discussed with patients as an option to
treat lower volume invasive disease, and offered
as an alternative for those patients with muscleinvasive disease who refuse cystectomy or are
precluded for consideration of cystectomy due to
severe comorbidities.
4. BLADDER-SPARING THERAPY
Combined modality therapy for the treatment of
muscle-invasive bladder cancer has been evaluated
in multiple single center studies and in some intergroup trials as well [122,123]. It arose as an option
for those wishing to undergo organ-sparing surgery
as well as an approach for those patients who are
poor candidates for surgery. There have been no
direct comparative trials between radical cystectomy
and organ-sparing approaches. The majority of treatment plans have been similar to those originally proposed by the MGH group which consists of complete
transurethral resection of the tumor, induction
chemotherapy, and possible radiation, which is followed by a clinical re-evaluation. Those with a complete response are consolidated with further
chemotherapy and radiation.
The overall 5-year survival rate for patients so treat-
231
RECOMMENDATIONS
I. INITIAL CONSIDERATIONS
techniques.
1. Retrospective analysis of cystectomy series suggests that time to definitive treatment may have an
independent impact on pathology and survival
outcomes. An effort to treat patients within 12
weeks of diagnosis is suggested to optimize outcomes, with the realization that medical optimization of the high-risk patient takes precedence
(Level 3, Grade B).
Cystectomy can be applied in the salvage setting
and in the case of evident adenopathy with reasonable results and higher complication rates.
Metastasis resection can be considered in select
cases (Level 3, Grade B).
2. Surgical factors such as the reduction in positive
soft tissue margins and extent of lymph node dissection can have an influence on 5-year survival
and local recurrence. All efforts to obtain negative
margins should be made at the time of surgery as
well as an effort to remove 10 or more nodes during the procedure. Heavily pretreated patients,
those with significant comorbidity demanding
expedient surgery, and those patients with
anatomically sparse nodes may not meet these
surgical criteria (Levels 2 and 3, Grade A/B).
2. Older patients with significant comorbidity can
demonstrate surgical outcomes similar to younger
patients at surgical centers of high volume.
Patients should not be rejected as surgery candidates only on the basis of chronological age.
More involved measures of comorbidity may provide a better measure of clinical outcomes than
classic anesthesia evaluations. Clinical pathways
may streamline care and provide cost-effective
measures for providing service. It remains to be
seen if they improve outcomes (Level 3, Grade B).
3. At this time the preponderance of data suggest that
a well-performed pelvic lymph node dissection
contributes little in the way of surgical morbidity
and clearly aids in surgical staging. It is possible
that it adds to the overall therapeutic effect of the
surgery, especially in lower volume nodal disease.
The value of higher level dissection (above the
common iliac vessels) remains to be determined.
3. At the current time there are no prospective data
regarding tumor markers in muscle-invasive bladder cancer to guide therapeutic decision making.
Routine tissue staining for biomarkers for purely
clinical decisions is not recommended. This is due
to the lack of standardization regarding the interpretation of staining as well as the lack of prospective data. Prospective trials incorporating marker
data should be supported and encouraged. Newer,
putative markers for muscle-invasive disease
(both tissue and serum) are emerging and warrant
prospective validation (Level 3, Grade B).
4. Frozen section pathology at the time of cystectomy can identify those patients of higher risk of
subsequent upper tract disease and potential poor
outcomes, yet does not affect anastomotic integrity or anastomotic recurrence in the overwhelming
majority of cases. It is a simple adjunct to the general procedure that should not be discouraged
(Level 3, Grade B).
II. RADICAL CYSTECTOMY
5. In relatively young and sexually active patients
with organ-confined bladder cancer, nerve- and
seminal-sparing cystectomy can be done with satisfactory preservation of function, yet the potential for clinical outcome for cancer control
remains to be determined. It should currently be
performed in very select cases (Level 3, Grade B).
1. Radical cystectomy and bilateral pelvic lymph
node dissection is the standard of care for muscleinvasive bladder cancer. The overall disease-specific survival for organ-confined disease is in the
70% to 85% range over 5 years and does not show
significant deterioration over a period of 10 years.
Similarly, extravesical disease and node-positive
disease demonstrate 5-year survival in the 50% to
60% range and 30% range, respectively, with sustained responses over a decade. These findings are
not matched or exceeded by other modalities.
6. In the absence of bulky disease or the suspected
involvement of gynecologic organs, the preservation of gynecologic organs in younger female cystectomy patients is advised (Level 3, Grade B).
7. Patients should be followed at short intervals over
the first 2 years beyond their surgery. Monitoring
should include biochemical monitoring, imaging
of the chest, abdomen, and pelvis, and monitoring
of the retained urethra (Level 3, Grade B).
Patients should be counseled about the significant
proportion of minor (30%) and major (3%-5%)
complications associated with surgery as well as
the 1% to 3% surgical mortality rate. Blood loss
may be lessened with new stapling and cautery
232
III. OTHER THERAPIES FOR MUSCLEINVASIVE BLADDER CANCER
1. Partial cystectomy remains an appropriate option
for treatment of muscle-invasive bladder cancer
on initial presentation in a small group (3%-5%)
of patients. It is particularly applicable to small
lesions in the dome of the bladder, and has a role
in the consolidation of neoadjuvant chemotherapy
in a small proportion of patients. Overall 5-year
survival is approximately 60%-70% and is difficult to compare to radical cystectomy series.
Patient selection is a critical factor to clinical success (Level 3, Grade B ).
2. Radical transurethral resection of muscle-invasive
bladder tumors is an acceptable alternative to cystectomy in a select proportion of patients demonstrating muscle-invasive disease. Repeat TUR
with downstaging to pT0 is important to assure a
reasonable long-term outcome. Aggressive early
and continued surveillance is mandatory (Level 3,
Grade B). Studies correlating molecular markers
and outcomes would be useful (Level 3, Grade B).
3. Minimally-invasive techniques for the treatment
of muscle-invasive bladder cancer are feasible and
should continue to be explored by groups with a
high overall level of expertise in laparoscopic and
robotic surgery. Besides improvements in blood
loss, the ability to identify true advantages of
these techniques in treating this disease will
require meticulous longer-term follow-up of larger cohorts of patients (Levels 3 and 4, Grade B/C).
4. Multimodal organ-sparing therapy should be discussed with patients as an option to treat lower
volume invasive disease, and offered as an alternative for those patients with muscle-invasive disease who refuse cystectomy or are precluded for
consideration of cystectomy due to severe comorbidities (Level 3, Grade B).
233
co-morbid disease on cancer control and survival following radical cystectomy. J Urol Jan;169(1):105-9, 2003.
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117. Roosen JU, Geertsen U, Jahn H, Weinreich J, Nissen HM. Invasive, high grade transitional cell carcinoma of the bladder treated with transurethral resection. A survival analysis focusing on
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120. Herr HW. Transurethral resection of muscle-invasive bladder
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121. Solsona E, Iborra I, Ricos JV, Monros JL, Casanova J, Calabuig
C. Feasibility of transurethral resection for muscle infiltrating
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AF, Efird JT. Selective preservation by combination treatment
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237
238
Committee 7
Urinary Diversion
Chair
R. E. HAUTMANN (GERMANY)
Members
H. ABOL-ENEIN (EGYPT)
K. HAFEZ (USA)
I. HARA (JAPAN)
W. MANSSON (SWEDEN)
R. D. MILLS (UK)
J. D. MONTIE (USA)
A. I. SAGALOWSKY (USA)
J. P. STEIN (USA)
A. STENZL (GERMANY)
U. E. STUDER (SWITZERLAND)
B. G. VOLKMER (GERMANY)
239
CONTENTS
2. PREREQUISITES
I. GENERAL ASPECTS OF URINARY
DIVERSION
3. THE KOCK POUCH
4. THE INDIANA POUCH
1. INDICATIONS, CONTRAINDICATIONS, AND
PATIENT SELECTION
5. APPENDICEAL OUTLET
6.COMPLICATIONS OF CONTINENT
CUTANEOUS URINARY RESERVOIRS
2. INTESTINAL TISSUES AS SUBSTITUTES FOR
THE BLADDER – THE PHENOMENON OF
MATURATION
7. SPECIFIC COMPLICATIONS
8. THE INTUSSUSCEPTED KOCK ILEAL
NIPPLE: A TECHNIQUE OF THE PAST
3. DETUBULARIZATION
4. WHICH GUT SEGMENT SHOULD BE USED?
9. REVISION SURGERY FOR NIPPLE FAILURES
5. METABOLIC CONSEQUENCES
IV. INCONTINENT URINARY
DIVERSION
6. POSTOPERATIVE REHABILITATION (FIRST
30 DAYS)
7. LONG-TERM FOLLOW-UP
1. CUTANEOUS URETEROSTOMY
8. QUALITY OF LIFE AFTER RADICAL
CYSTECTOMY
2. CONDUIT DIVERSION
V. ANAL SPHINCTERCONTROLLED URINARY
DIVERSION
9. RENAL FUNCTION AFTER URINARY DIVERSION
10. URINARY TRACT INFECTION
1. ANAL SPHINCTER-CONTROLLED BLADDER
SUBSTITUTES WITHOUT FECAL
DIVERSION
II. ORTHOTOPIC
RECONSTRUCTION
2. ANAL SPHINCTER-CONTROLLED BLADDER
SUBSTITUTES WITH PARTIAL FECAL
DIVERSION
1. PATIENT SELECTION
2. IS REFLUX PREVENTION NECESSARY?
3. UPPER TRACT SAFETY (LONG-TERM)
VI. PALLIATIVE DIVERSIONS
4. CONTINENCE
5. ONCOLOGIC SAFETY
1. INTRODUCTION
6. SEXUALITY-PRESERVING ORTHOTOPIC
RECONSTRUCTION
2. PERCUTANEOUS NEPHROSTOMY
VII. OUTLOOK
7. SPECIFIC COMPLICATIONS
8. TYPES OF ORTHOTOPIC RECONSTRUCTION
WITH CONFIRMED EXPERIENCE BY
OTHER CENTERS
VIII. CONCLUSIONS
RECOMMENDATIONS
III. CONTINENT CUTANEOUS
DIVERSION
APPENDICES 1, 2, 3
REFERENCES
1. INDICATIONS
240
Urinary Diversion
R. E. HAUTMANN
H. ABOL-ENEIN, K. HAFEZ, I. HARA, W. MANSSON, R. D. MILLS, J. D. MONTIE,
A. I. SAGALOWSKY, J. P. STEIN, A. STENZL, U. E. STUDER, B. G. VOLKMER
ly of Grade C. Grade C recommendation is given
when expert opinion is delivered without a formal
analytical process, such as by Delphi. In order to
check the validity of the consensus reached by the
diversion group the chairman has asked the committee members after the final consensus meeting to disclose experience, surgical volume, and types of
diversions used at their home institutions. The result
is presented in Table 1 and is in full harmony with
the recommendations the panel has made.
The goals of urinary diversion following cystectomy
have evolved from simple diversion and protection
of the upper tracts to functional and anatomical
restoration as close as possible to the natural preoperative state. This evolution of urinary diversion has
developed along the 3 distinct paths of incontinent
cutaneous diversion (conduit); continent, cutaneous
diversion (pouch); and, most recently, continent urinary diversion to the intact native urethra (neobladder, orthotopic reconstruction). During the last 15
years, orthotopic reconstruction has evolved from
“experimental surgery” to “standard of care at larger
medical centers” to the “preferred method of urinary
diversion” in both sexes. The ileal conduit was
described in 1950 by Bricker and has remained a
standard urinary diversion against which others are
judged. During the last decade, the time-honored
conduit has given way to the increasingly frequent
use of orthotopic reconstruction.
I. GENERAL ASPECTS OF URINARY
DIVERSION
1. INDICATIONS, CONTRAINDICATIONS,
PATIENT SELECTION
AND
a) Substantial Change in Paradigm
The goal of patient counseling about urinary diversion should be to determine the method that is the
safest for cancer control, has the fewest complications in both the short- and long-term, and provides
the easiest adjustment for the patients’ lifestyle, supporting the best quality of life. The paradigm for
choosing a urinary diversion has changed substantially. Now all cystectomy patients are candidates for
a neobladder, and we should identify patients in
whom orthotopic reconstruction may be less ideal.
The International Consultation on Urological Diseases (ICUD) consultations have looked at published
evidence and produced recommendations at various
levels. For proper assignment to levels of evidence,
one has to consider study design (prospective, retrospective), number of patients enrolled, if the study
cohort consists of all patients available or not, type
of assessment tool and its psychometric properties
(validity/reliability), and response rate. Unfortunately, not a single randomized controlled study within
the field of urinary diversion exists. Consequently,
almost all studies used in this report are of Level 3
evidence (incorporates Oxford 3a, 3b, and 4) - good
quality retrospective studies or case series - or Level
4 evidence (incorporates Oxford 4) including expert
opinion based on “first principles” research. Therefore, the grades of recommendations given are most-
The proportion of cystectomy patients receiving a
neobladder has increased at medical centers to 50%
to 90% [1-4].
b) Patient Selection Criteria: Absolute and Relative
Contraindications
An absolute contraindication to continent diversion
of any type is compromised renal function as a result
241
Table 1. Urinary Diversions Performed by the Authors
symptoms (such as hematuria or pain) or uremia.
Second, patients undergoing total cystectomy but not
urinary diversion using intestinal segment are candidates for palliative urinary diversion. Patients with
severe bowel adhesion or disease or patients who
need short and less invasive surgery due to medical
conditions need palliative urinary diversion.
of long-standing obstruction or chronic renal failure,
with serum creatinine above 150 to 200 µmol/L.
Severe hepatic dysfunction is also a contraindication
to continent diversion. Patients with compromised
intestinal function, particularly inflammatory bowel
disease, may be better served by an incontinent
bowel conduit. Orthotopic reconstruction is also
absolutely contraindicated in all patients in whom
simultaneous urethrectomy is indicated based on
their primary tumor [5,6]. The role of relative contraindications and comorbidities is steadily decreasing. However, some of them, such as mental impairment, external sphincter dysfunction, or recurrent
urethral strictures, deserve serious consideration.
2. INTESTINAL TISSUES AS SUBSTITUTES FOR
THE BLADDER – THE PHENOMENON OF
MATURATION
a) Intestinal Tissues as a Substitute for the Bladder
It would be ideal if the transposed gut segment over
time lost its own organization and intrinsic control,
and the smooth muscle changed properties to
become more like normal detrusor and was reinervated through the sacral parasympathetic micturition
pathway, so that it could contribute to bladder emptying. Potentially the greatest difference between
conduit and neobladder is that the conduit functions
as a somewhat longer ureter, whereas a neobladder is
a substitute for the detrusor. Understanding orthotopic bladder replacement in full requires understanding the phenomenon of maturation. Unlike a
conduit, the motor and pharmacologic responses of a
neobladder change dramatically towards that of the
original bladder [9]. Maturation of a neobladder
takes anywhere from a few weeks or several months
to up to 8 years [9]. Approximately 4 to 6 weeks after
surgery, patients with conduits are usually into a
well-established routine.
Paramount to success of anal sphincter-controlled
bladder substitutes is an adequate anal sphincter
mechanism. Inability of the patient to retain 400 to
500 mL in the upright position for 1 hour is a contraindication [7]. Patients with neurogenic bladder
are not suitable candidates either, as there may be
associated anal sphincter dysfunction [8].
Urologists should first consider permanent urinary
diversion for patients who undergo total cystectomy
due to invasive bladder cancer. In fact, less attention
has been directed to palliative urinary diversions in
the treatment of bladder cancer. However, mainly in
2 situations, this type of urinary diversion has significant meaning for patients with bladder cancer. First,
patients who cannot have total cystectomy because
of advanced stage or poor general condition sometimes require urinary diversion due to uncontrollable
242
b) Gut Muscle as a Substitute for the Detrusor
functional outcome. In contrast, in the tubular segments the ICC-MP, ICC-DMP, and circular muscle
layer retrained normal features for up to 3 years.
After this, ICC-DMP were lost, DMP nerve fibers
were scant, and the circular muscle layer appeared
degenerate, but the ICC-MP remained intact. It was
apparent that those reservoirs maintaining a normal
ICC-MP population developed pressure waves and
those segments with intact ICC-DMP had a contractile response to distention. Whether these physiological changes are a result of the ileal segment chronically functioning as a reservoir or the product of the
surgical interruption of myoneural networks and the
ICC syncytium is unclear (Table 2).
1. STRUCTURAL CHANGES
Interstitial cells of Cajal (ICC), so named for their
identification with the interstitial cells observed by
Cajal in the mammalian small intestine [10], possess
a morphology and location specific for each of the
specialized regions of the gastrointestinal tract [11].
ICC are considered of primary importance for gastrointestinal motility and are accepted as the intestinal pacemaker cells. In the small intestines of
humans, ICC are located in 2 different muscular layers [12]. One population (the ICC-MP) is located
between the longitudinal and circular muscle layers
and has a relationship to the myenteric plexus (MP).
The presence of this cell type has been correlated
with slow-wave activity and found to be of fundamental importance for the occurrence of normal peristalsis [13]. The second ICC population (the ICCDMP) is specific to the small intestine. It is located
between the innermost inner circular muscle layer
and outermost subdivisions of the circular muscle
layer, in association with the deep muscular plexus
(DMP), and its role might be related to motility specific to this gut area. Faussone-Pellegrini and
coworkers have studied motor patterns, intraluminal
pressures, volume capacity, and histoanatomic characteristics in full-thickness specimens from orthotopic ileal bladders removed during corrective
surgery [14]. In the detubularized segments 1 to 6
years after reconstruction, the ICC-MP were scarce,
and intact ICC-DMP cells and DMP nerve fibers
were not seen. Furthermore, the innermost circular
muscle layer could not be identified. This loss of
structural organization was associated with a better
2. PHARMACOLOGIC CHANGES
In experimental animals, it has been possible to follow the changes in function of implanted segments
after their incorporation into the bladder, to see if
they do indeed become more like detrusor in their
function. Batra et al. have looked in detail at the
changes in the pharmacologic properties of muscle
strips taken from the ileal segment of augmentation
cystoplasty in rabbit models [15]. The contractile
response of the ileal segment changed from the
response typical of normal ileum to a phasic
response more characteristic of detrusor. Furthermore, the normal ileal relaxation reverses to a contractile response similar to that seen in the detrusor,
after incorporation into the cystoplasty. The number
of muscarinic receptors in the ileal segment
decreased after incorporation. Further experiments
comparing strip responses from tubular and detubularized segments showed that these changes were
more profound in detubular cystoplasties, compati-
Table 2. Distribution of Interstitial Cells of Cajal (ICC) in Ileal Reservoirs (Humans) and Motor Response Characteristics
243
ble with the concept that the surgical interruption of
myoneural networks is the primary signal for the
transformation from ileal-type to detrusor-type
responses, as opposed to exposure to urine or chronic functioning as a reservoir.
Table 3. Structural and Ultrastructural Changes in Ileal
Neobladder Mucosa
Early (< 1 year)
Inflammatory
Late (1-4 years)
Regressive
c) Gut Mucosa as a Substitute for the Urothelium
Infiltration of lamina propria
Villous atrophy
Most research on transposed gut segments has
focused on the potential for malignancy arising in the
reconstructed bladder substitute. This will not be discussed here.
Rarefaction of terminal web
Shortening crypts
Goblet cell hyperplasia
Goblet cells decreased
(> 4 years)
Reduction of microvilli
- toxic effect of urine
Flat mucosa
- low pH
Stratified epithelium
• STRUCTURAL AND ULTRASTRUCTURAL CHANGES
NEOBLADDER MUCOSA
IN
- ischemia
Systematic follow-up of the effects of the ileal
mucosa in patients with continent reservoirs reveals
constant and homogeneous changes. They seem to
be directly related to the time since surgery and can
be subdivided into early and late. From these observations and those published previously, it seems evident that when the ileum is removed from its absorptive function and must respond to a chronic irritative
stimulus, the result is biphasic; the first inflammatory phase is followed by a second regressive phase in
which the epithelium tends to assume a morphology
similar to the urothelium, more adapted for coating
and protective functions than for absorption. Therefore, it is not surprising that it should be the structures responsible for absorption (brush border and
villi) that suffer the most damage. Considering that
in a normal ileum the villi increase the absorptive
surface eightfold in comparison to a flat surface,
their atrophy greatly reduces the area of absorption
and, consequently, the risk of metabolic alterations.
Paneth’s cells (which produce digestive enzymes)
and goblet cells seem more tolerant to the prolonged
contact with urine and the regressive phenomena
appear significantly later. Because the villi and crypta are markedly shorter, the ileal mucosa tends to
become linear (Table 3). This also explains the alternation of areas in which cells with few microvilli
(corresponding to the primitive surface epithelium)
are predominant with others in which goblet cells
(corresponding to the primitive glandular epithelium) are predominant. After four years of follow-up,
the areas of villous atrophy predominate, Paneth’s
and goblet cells are scanty, and only few residual
glands are visible. The resulting epithelium has lost
its absorptive and secretory functions to acquire the
function of a urinary reservoir. Electron microscopy
and enzyme histochemistry also showed that in the
epithelial cells there was a reduction in the number
of cell organelles and a decreased metabolic activity
- lack of contact with
intestinal content
[16]. Progressive mucosal atrophy has been observed
in continent colonic reservoirs. They show similar,
although much less severe, changes of the microvilli
[16,17]. Follow-up studies in patients with ileal conduits also showed atrophic changes with reduction of
the villous height, although there are wide variations
between different authors and individual patients
[18].
The final result of the process of maturation can be
summarized as follows:
• Structure and pharmacologic response of the
implanted ileum (not colon) changes to detrusortype responses.
• Structural and ultrastructural changes in ileal (not
colonic) mucosa lead to a primitive surface and
glandular epithelium similar to urothelium.
• The transformation of the ileal mucosa minimizes
the risk of metabolic complications. Consequently, Mother Nature has engineered a new bladder
almost as good as the one given initially [19].
3. DETUBULARIZATION
Although it would be ideal if the bowel segment
could contribute to voluntary voiding, in reality this
does not seem to happen, thus, a highly compliant
neobladder is the desired outcome [20]. Detubularized bowel segments provide greater capacity at
lower pressure and require a shorter length of intestine than do intact segments. Four factors account for
their superiority: their configuration takes advantage
of the geometric fact that volume increases by the
244
square of the radius so that a pouch has a larger
diameter than a tube; they accommodate to filling
more readily because, as La Place´s law states, the
container with the greater radius and, thus, the
greater mural tension, will hold larger volumes at
lower pressure; compliance is superior to that of the
tubular bowel; and contractile ability is blunted by
the failure of contractions to encompass the entire
circumference [21].
decreased kidney function and increased risk for
metabolic disorders [28,29]. An obvious advantage
of the sigmoid reservoir is its ease of accessibility.
However, there is the substantial disadvantage of
high reservoir pressures as compared to cecum or
ileum that is confirmed by most urodynamic studies
[30-32]. We recommend using a sigmoid reservoir
only in cases in which ileum or right colon are not
available [2]. An advantage of the ileocolonic reservoir is its greatest initial volume as a reservoir. However, it requires mobilization of the entire right colon
and is potentially the most tedious procedure to perform [33]. The greatest disadvantage of the procedure is the loss of the ileocecal valve. There is also a
greater risk of vitamin B12 deficiency secondary to
resection of the terminal ileum.
These theoretical considerations are consistent with
clinical observations showing that detubularization
increases reservoir capacity substantially, and delays
the onset and reduces the amplitude of the pressure
rise produced by contractions. These findings
account for the markedly improved nocturnal continence (80% vs. 17% at 2 years), the longer voiding
intervals (4 vs. 2.5 hours at 1 year), and the predisposition to urinary retention (25% vs 0% at 1 year)
with detubularized versus tubularized bladder substitution. Altering the shape of a reservoir from spherical to ellipsoid is calculated to have only a slight
effect on its mechanical characteristics. Consequently, the essence of detubularization is to create a
reservoir with high capacity, while shape is of secondary importance [22].
Most investigators have reported on one single type
of diversion. Santucci et al. performed 6 different
continent urinary reservoir operations and revealed
remarkably different continence rates and urodynamic data. Their experience suggests that neobladders
composed of stomach or sigmoid should be used
only under unusual circumstances because of the
high rates of incontinence [32]. Of course, other
patient and surgeon issues might supersede these
guidelines. Surgeon preference, length of surgery,
ease of construction, potential need for revision, differences in body image, and other patient characteristics are among the many factors that must be considered when choosing which type of orthotopic
reconstruction to provide each individual patient.
4. WHICH GUT SEGMENT SHOULD BE USED
a) Biological Consequences of Exposing Gut
Mucosa to Urine
Intestinal segments vary in handling of solutes.
Length of bowel segment, surface area, duration of
urinary exposure, solute concentration, pH, renal
function and urine osmolality all play a role. The
reservoir surface is exceedingly difficult to estimate.
There is no difference between ileal and colonic
mucosa in regard to sodium absorbing capacity.
However, in the colon, chloride absorption and
bicarbonate excretion are more pronounced, and
there is increasing evidence to suggest that inherent
chloride absorption is maintained when in contact
with urine [16,23-27]. Therefore, it may be preferable to use ileum rather than colon for bladder reconstruction to reduce the risk of hyperchloremic acidosis, particularly in the presence of renal impairment.
There are clear differences between ileum and colon
in regard to metabolic consequences (see Section
I.2.c: Gut Mucosa as a Substitute for the Urothelium), but this is only one consideration when planning orthotopic reconstruction. However, due to the
reduced absorption of electrolytes in ileal urinary
reservoirs, it seems that ileum is preferable to large
bowel for storing urine, at least in patients with
b) Capacity and Pressure Characteristics of Reservoirs (Table 4)
Berglund et al. have studied the volume capacity and
the pressure characteristics of 3 types of intestinal
reservoirs - the continent ileostomy, the continent
ileal urostomy, and the continent cecostomy - at
varying intervals after surgical construction of the
reservoirs [34]. The volume increases of the ileostomy and the urostomy reservoirs were almost identical but were significantly greater than that of the
cecal reservoir. The basal pressure was low in all
types of reservoirs, although somewhat higher in the
cecal reservoir at greater filling volumes. In the ileal
reservoirs, motor activity appeared at a filling volume of about 40% of the maximal capacity, whereas
in the cecal reservoir motor activity was recorded at
all filling levels. The motor activity increased with
greater volumes. The amplitude of the highest pressure wave in the cecal reservoir was twice as high as
that of the ileal reservoirs. The motor activity of the
cecal reservoir, calculated in 2 different ways, was
10 to 20 times greater than in the ileal reservoirs.
245
Table 4. Capacity and Pressure Characteristics of Reservoirs
Ileum
Colon
Volume increase
- Initially
- Late
Advantage
Advantage
Capacity
- First contraction
- Maximum contraction
Advantage
Advantage
Involuntary contractions
- Maximum amplitude
Advantage
Motor activity (calculated)
10 – 20x higher
Distensibility
Ileum (ICL) > Colon (CCL) > Ileum (ILL) > Colon (CLL)
Advantage
Compliance
Advantage
CCL - colonic circular layer; CLL - colonic longitudinal layer; ICL - ileal circular layer; ILL - ileal longitudinal layer
An interesting comparison of the properties of different gut smooth muscles was made by Hohenfeller
et al., who examined the ileal and cecal segments
incorporated into a canine model of the Mainz bladder substitution. Sonomicrometry transducers were
implanted in the circular and longitudinal muscular
layers to allow measurements of their properties. It
was found that the circular ileal layer was most distensible, followed by the colonic circular and the
longitudinal ileal layers. The longitudinal layer of
the colonic segment was relatively indistensible [35].
Clinically significant cystoplasty contractions are
arbitrarily defined as those 40 cm H2O in amplitude
or higher that begin to occur at low volumes (less
than 200 mL). The incidence of such contractions
was 70% for tubular ileocystoplasties, 36% for tubular right colon, 10% for detubularized colon, and
none in the patients with detubularized ileocystoplasties [36]. The detubularized ileal reservoir for
either continent stomal diversion or bladder replacement would seem to constitute the ideal low pressure
reservoir.
antidiuretic hormone release. This metabolic disturbance results in highly concentrated urine from
which the colonic mucosa will absorb more sodium
and chloride. Classically, these patients become acidotic and with close scrutiny all have at least a mild
degree of metabolic acidosis following continent
diversion using colonic segments [38]. The principal
mechanism leading to the production of acidosis is
thought to be ammonium reabsorption. Ammonia,
ionized ammonium, and chloride are reabsorbed
when ileum or colon is exposed to urine [38,39]. The
acid load comes mainly from the reabsorption of
ammonium chloride. Quantitatively, hydrogen reabsorption is minimal and bicarbonate secretion is
exceeded many times by ammonium reabsorption.
Ammonia may diffuse freely across the bowel
mucosa, and, as urinary pH increases, absorption
will increase. However, there is evidence that reabsorption of ionized ammonium occurs, which can be
seen at luminal pH 5 when ionized ammonia is present in only small amounts. Also, in brush border
membrane studies, ammonium transport can be
demonstrated against an ammonia concentration gradient [40]. If the sodium concentration in a urinary
reservoir is increased, ammonium absorption is
decreased. Recent evidence has suggested that
ammonium absorption may occur through substitution for sodium in the sodium-hydrogen antiport with
the ammonium ion acting as a competitive inhibitor
of sodium uptake [41]. There is also evidence of ionized ammonium absorption through potassium channels, although this is not thought to contribute significantly to acidosis [40]. Current treatment of
5. METABOLIC CONSEQUENCES
a) Hyperchloremic Metabolic Acidosis
In 1950, Ferris and Odel were the first to describe the
unusual electrolyte pattern characterized by
hypokalemia, hyperchloremic acidosis, and absorption of ammonia in patients with ureterosigmoid
diversion [37]. The use of colon for urinary reservoirs may lead to serum hyperosmolarity and subsequent decreased aldosterone release with increased
246
pH and bicarbonate do not exclude a severely compensated metabolic acidosis, and blood gas analysis
and body weight measurements are required. If possible, these patients should not be given hydrogen
antagonists or proton pump inhibitors as they will
contribute to systemic acidosis by preventing hydrogen excretion with subsequent bicarbonate preservation on the cellular side [29].
hyperchloremic metabolic acidosis involves alkalizing agents and/or blockers of chloride transport. Oral
sodium bicarbonate is effective in restoring normal
acid base status, but intestinal gas formation can be a
problem, and the dose is not easily predictable.
Alternatively, sodium citrate may be given but the
taste is unpleasant. Sodium supplements may
increase blood pressure or cause fluid retention and
pulmonary edema in patients at risk. If excessive
sodium loads are undesirable, chlorpromazine or
nicotinic acid may be used, although they are also
not without significant side effects. They act through
inhibition of cyclic adenosine monophosphate, thereby impeding chloride transport, and alone will not
correct acidosis but will alleviate the situation,
allowing a reduced dose of alkalizing agent [40].
Hypocalcemia and/or hypomagnesemia severe
enough to cause symptoms do occur, but they are
infrequent complications of urinary intestinal diversion. Hypocalcemia is a consequence of depleted
body calcium stores and excessive renal wasting.
The chronic acidosis is buffered by carbonate in the
bone with subsequent release of calcium in the circulation. The kidneys clear the released calcium
resulting in a gradual decrease in body calcium
stores. There is also an inhibition of renal tubular
absorption of calcium directly by sulfate and
enhanced by acidosis. Treatment consists of calcium
therapy [46].
The key to successful management is proper diagnosis by exclusion of urinary infection and sepsis, and
awareness of the salt-losing syndrome. Proper treatment includes catheter reinsertion to ensure good
drainage and to minimize further chemical reabsorption, rehydration with intravenous normal saline, and
correction of acidosis with sodium bicarbonate.
Patients with incomplete emptying and those with
reduced renal function are most vulnerable to these
metabolic problems [43,44].
Magnesium deficiency is usually due to nutritional
depletion but it may be a result of renal wasting. The
altered calcium metabolism, acidosis, and sulfate
metabolism all interfere with renal tubular magnesium reabsorption [46].
b) Hypokalemia and Other Electrolyte
Abnormalities
c) Altered Sensorium
Altered cerebration may occur as a consequence of
magnesium deficiency, drug intoxication, or abnormalities in ammonium metabolism. Symptoms due
to magnesium deficiency are usually observed when
magnesium concentration is less than 1 mEq/L. The
symptoms are due to neuromuscular dysfunction and
consist of personality changes that may lead to delirium and psychosis, muscular weakness, tremors,
and, rarely, tetany. Seizures and death may occur if
the deficiency persists. The most common cause of
an altered sensorium is the consequence of altered
ammonia metabolism [42].
Hypokalemia and total body depletion of potassium
may be seen with ileal and colonic urinary intestinal
diversion, although more frequently with the latter as
ileal segments absorb more potassium. In one study,
patients with ureterocolonic diversion had a 30%
decrease in total body potassium and those with an
ileal conduit had up to a 14% decrease [45].
The potassium depletion is probably due to renal
potassium wasting as a consequence of renal damage, osmotic diuresis, and gut loss through intestinal
secretion. The latter probably has a relatively minor
role quantitatively. It has been shown that ileal segments, when exposed to high concentrations of
potassium in the urine, reabsorb some of the potassium, whereas colon is less likely to do so [26]. Therefore, treatment with potassium citrate is often most
appropriate for patients with colonic reservoirs.
d) Disorders of Hepatic Metabolism
When intestine is interposed in the urinary tract,
there is a marked increase in the absorption of
ammonia into the portal circulation due to the
increased load of ammonia from the urine. The liver
clears the increased ammonia load resulting in
imperceptible alterations in its serum concentrations.
Ammonia is incorporated into the ornithine cycle to
create urea. It has been shown that the liver rapidly
adapts by increasing its capacity for ureagenesis
[47]. This hepatic reserve for ammonia clearance is
Acid base balance should be monitored regularly in
patients with continent diversion, particularly in the
early postoperative period. One should have a high
index of suspicion if patients with urinary diversion
have nonspecific illness. Acidosis and electrolyte
disturbance should be excluded early. Normal serum
247
great, and it is unlikely that acute changes in ammonia loads result in significant alterations in serum
ammonia levels when hepatic function is normal.
However, small amounts of endotoxin can significantly affect hepatic metabolism and transport [48].
Hyperammonemic encephalopathy has been reported most commonly in patients with ureterosigmoidostomy [49]. The patients who suffer ammoniogenic coma with clinical normal liver function generally have a significant infection with a urease-producing bacterium. Often the infection is associated
with obstruction of the urinary tract. The direct
access of bacteria and endotoxin to the liver via the
portal circulation results in altered hepatic
metabolism without significant alterations in hepatic
enzyme concentrations [42].
ed that monitoring levels of vitamin B12 alone
underestimates the true incidence of tissue cobalamin deficiency [56]. Abnormal levels of vitamin
B12, methylmalonic acid, or homocysteine were
observed in 14%, 29%, and 43% of 12 patients with
ileal neobladders at a mean follow-up of 4.6 years
(range 0-10 years). Other investigators report that
holotranscobalamin levels are more accurate and
specific indicators of tissue cobalamin deficiency
and are decreased in one-third of patients in longterm follow-up [58]. Still other investigators report
that routine administration of vitamin B12 every 6
months prevents vitamin B12 deficiency in all
patients at 10 year follow-up [57]. The merits of
monitoring vitamin B12 levels versus routine chronic supplementation may be debated from a cost and
practical standpoint. However, as survival after treatment for bladder cancer steadily improves and the
number of patients with continent urinary diversions
increases, this issue may assume increasing importance.
e) Abnormal Drug Metabolism
Drugs secreted unchanged in the urine and absorbed
by the intestinal tract are most likely to lead to problems. Of particular interest are chemotherapeutic
agents used in the treatment of bladder cancer.
Methotrexate toxicity in patients with ileal conduits
is well recognized [50,51]. Patients with continent
diversion receiving chemotherapy should be monitored closely, stay well-hydrated, and have the reservoir drained during treatment. Other drugs reported
to be absorbed from intestinal segments in the urinary tract include phenytoin, theophylline, and
antibiotics [25,52]. Diabetics appear to have an
enhanced ability to absorb glucose from intestinal
reservoirs and, therefore, screening with urine tests
may be inaccurate, and so surveillance of known diabetics should rely on blood tests [53].
g) Decreased Linear Growth
There is considerable evidence to suggest that urinary intestinal diversion has a detrimental effect on
growth and development. Long-term follow-up for
rats with unilateral ureterosigmoidostomy demonstrated significantly decreased femoral bone length
compared to non-diverted controls [60]. Numerous
clinical studies have demonstrated decrease in linear
growth in children after ileal bladder augmentation
[61,62].
h) Bone Demineralization
A worrying potential long-term effect of urinary
intestinal diversion is bone demineralization, which
has been most clearly demonstrated in children with
rickets and adults with osteomalacia after ureterosigmoidostomy [63,64]. In these conditions, bone mineral loss is replaced by osteoid, resulting in
decreased bone strength. The etiology is complex but
long-term changes in acid base balance are likely the
major contributory factor. Chronic acidosis may
affect the skeleton in 3 ways:
f) Vitamin B12 Deficiency
Vitamin B12 absorption occurs primarily in the terminal ileum. Thus, use of ileum, and, to a lesser
degree, the ileocecal segment, for orthotopic
neobladder construction may lead to chronic vitamin
B12 deficiency in some patients. Chronic vitamin
B12 deficiency is insidious and may result in irreversible neurologic and hematologic sequelae. The
absolute prevalence and clinical significance of this
entity in neobladder patients is undetermined. Vitamin B12 absorption decreases with age and with
declining renal function. From baseline levels,
depletion of body stores of vitamin B12 requires 3 to
5 years. All of these variables account for the wide
range of vitamin B12 deficiency reported (0%-33%)
in various series [42,54-59]. Neobladders consisting
entirely of colon segments have been reported not to
affect vitamin B12 levels [54,59]. One group report-
a) Bone minerals, including calcium, carbonate and
sodium, act as buffers in exchange for hydrogen
ions, thus decreasing the skeletal calcium content
[65,66].
b) Acidosis impairs 1-hydroxylation of 25-hydroxycholecalciferol in the kidney and activated vitamin D
deficiency results in bone mineralization defects
[67].
248
c) Acidosis activates osteoclasts, resulting in bone
resorption [68]. In addition, there may be poor
intestinal absorption of calcium and vitamin D following ileal resection.
[73]. A recent study demonstrated significantly
decreased bone mineral density and increased urinary pyridinium cross-links associated with metabolic acidosis after Indiana and Kock pouch formation
[74]. Also, urinary diversion with the ileal Kock
reservoir reduced bone mineral density of the spine
and total skeleton compared to normal age matched
controls [75]. Additional prospective studies with
longer follow-up are required before the risks of
bone demineralization and subsequent fracture rate
associated with continent diversion are known. The
contradictory reports on bone mineral density following urinary intestinal diversion might be related
to different bone densitometers and lack of pediatric
normal data in first generation densitometers.
Patients who present with osteomalacia should have
acid base abnormalities corrected first, which may
relieve symptoms and lead to remineralization
[63,76]. If remineralization does not occur, further
treatment should be given with activated vitamin D
and calcium supplements [64].
Patients with preexisting renal disease will be more
prone to acidosis and also may have impaired activated vitamin D production secondary to tubular cell
damage, and so they are at particular risk. Changes in
acid base balance may be subtle, and, as experiments
in animals with urinary diversion have demonstrated,
oral supplementation with bicarbonate can prevent
demineralization in the absence of significant systemic acidosis [66]. Some institutions now recommend oral sodium bicarbonate when base deficit is
more than 2.5 mmol/L [69]. Patients may be asymptomatic, complain of pain in weight-bearing joints,
or present with fractures. Long-term follow-up of
patients with myelomeningocele with intestine in the
urinary tract has revealed an increased number of
fractures and intervention rate for spinal curvature
with increased incidence of non-union and delayed
healing compared to controls treated with intermittent catheterization [61]. This finding suggests that,
although severe defects in bone demineralization are
not often seen, it is likely that many patients have
subtle alterations in bone mineral density with prolonged follow-up after urinary intestinal diversion.
Women, who are susceptible to postmenopausal
osteoporosis, and young patients, who are growing
and may live with urinary diversion for many years,
seem to be at greatest risk. Laboratory tests may be
normal despite symptoms, although in general there
is reduced serum calcium and phosphate with elevated alkaline phosphatase [66,70]. Parathormone levels are usually not elevated and serum levels of activated vitamin D may be normal. Radiological
appearances are usually also normal. Bone densitometry is useful but may not detect subtle changes
without repeat testing. Bone biopsy may be the only
way to confirm diagnosis. Therefore, follow-up is
difficult, especially as the process takes many years.
With normal renal function, severe bone defects are
not common after continent diversion with ileal or
colonic reservoirs. The risk may be slightly higher
with colonic reservoirs as calcium re-uptake is less
efficient from colonic than ileal segments [70]. Follow-up studies have revealed contrasting findings.
Normal bone mineral density has been reported in
patients with orthotopic ileal reservoirs up to 17
years following urinary diversion [71,72]. Also, bone
mineralization was not affected in patients with continent cecal reservoirs followed more than 5 years
i) Mucus Production
Bowel mucosa secretes mucus made up of a glycoprotein core of long sequence amino acids with a
molecular weight of 2 to 20 million Daltons with
side chains of monosaccharides wrapped around the
protein core [77,78]. The glycoprotein core is made
by the rough endoplasmic reticulum of goblet cells.
In solution, the glycoprotein becomes hydrated and
viscous. Continent urinary diversions produce
around 35 grams of mucus per day [79]. In the early
postoperative period, the indwelling catheters must
be carefully irrigated to prevent initial mucus
buildup within the diversion [80,81]. Patients with
good spontaneous voiding and complete emptying
usually pass the mucus spontaneously in the urine. In
contrast, patients with incomplete emptying or those
performing CIC may need to irrigate to remove
retained mucus. Mucus accumulation may occur in
some neobladder patients with apparently normal
voiding. Some investigators report that an increase in
mucus production may be an early sign of urinary
infection and irritation in the diversion [82]. Early or
late mucus retention has been reported in 0.58% to
2% and in 3% of patients, respectively [1,83]. Nacetylcysteine and urea are effective mucolytic
agents [77,84,86]. N-acetylcysteine is a water-soluble thiol that reduces the disulfide bonds in the
mucus. In contrast, carbocysteine causes mucus precipitation rather than dissolution. Successful dissolution of a mucus plug in an ileal ureter has been
reported after initial instillation of 300 mL of 1% N-
249
eral care floor and managed with clinical pathways
[96]. Those patients admitted to the ICU had greater
resource utilization and longer hospital stays, but
tended to be sicker overall than the floor patients (as
measured by ASA score). The authors concluded that
initial postoperative cystectomy care could be safely
conducted on a general care floor, with ICU admission reserved for the sickest and most labor-intensive
patients. Postoperative medications should reflect
the need for prophylaxis, pain control, and management of a given patient’s comorbidities. Adequate
pain control enables early ambulation and deep
breathing, thus reducing the risks of deep venous
thrombosis and pulmonary complications. Epidural
catheters or patient-controlled analgesia are effective
means of individualizing delivery of pain medications [97]. Histamine blockers or proton pump
inhibitors should be used for prophylaxis against
ulcers, and either compression devices or low molecular weight heparin should be utilized for DVT prophylaxis. Incentive spirometry, coughing, and deepbreathing exercises help to minimize postoperative
respiratory complications. The routine use of nasogastric decompression is unnecessary. Cheatham et
al. compared patients with routine postoperative
nasogastric decompression with those in whom
nasogastric decompression was performed for clinical indications only; patients who did not receive a
routine nasogastric tube fared better in terms of complications such as fever, atelectasis, and pneumonia,
and advanced more quickly to a regular diet [98]. In
another study, patients who were given metoclopramide in association with early removal of the
nasogastric tube (within the first 24 hours after
surgery) had fewer episodes of atelectasis, more
rapid return of bowel function, and earlier ability to
tolerate a regular diet [99]. Inman et al. retrospectively analyzed 430 patients after cystectomy and
urinary diversion, and found that prolonged gastric
decompression was associated with delayed return of
bowel function and prolonged hospitalization [100].
Mohler and Flanigan showed that malnourished
patients had poorer outcomes compared with nutritionally optimized patients [101]. The authors found
that the need for nutritional support postoperatively
was associated with increased morbidity and mortality. Their results suggest that preoperative optimization of nutrition status is crucial.
acetylcysteine through a nephrostomy tube followed
by oral N-acetylcysteine 700 mg 4 times daily [87].
Irrigation of urinary diversions with N-acetylcysteine at smaller volumes and higher concentrations
(30 mL, 20%) also has been found to be effective
[77,79]. Urea appears to break the hydrogen bonds
within mucus and is faster and more potent than Nacetylcysteine [77,79,85]. In vitro, 12 grams urea per
100 grams mucus produced 90% and 100% dissolution of mucus within 5 minutes and 30 minutes,
respectively. Once a large mucus plug occurs, none
of the drugs may be effective, and manual evacuation
through a large resectoscope sheath is most effective
[88]. Oral therapy with ranitidine has been reported
to decrease mucus production in patients with urinary diversions [78]. However, in another prospective, randomized study of patients with urinary
diversions, neither taking ranitidine nor aspirin produced any change in mucus production [89].
Whether chronic adaptation of bowel mucosa incorporated into urinary diversions leading to decreased
mucus production occurs is controversial. Some
investigators report decreased mucus over time [90],
while others do not (Level 3, [91]). Ileal mucosa
appears to atrophy over time when exposed to urine
[92-94], while colonic mucosa is preserved and
retains its mucus and immunoglobulin secretory
capacities [95]. The minority of patients with recurrent mucus retention must be made aware of the
importance of this problem, should be instructed in
periodic catheter irrigation and mucus evacuation,
and should be offered a trial of medical therapy with
N-acetylcysteine or urea.
6. POSTOPERATIVE REHABILITATION (FIRST
30 DAYS)
There are 2 major goals in the early postoperative
period: to minimize postoperative complications and
to return the patient to the usual state of health.
a) Initial Postoperative Course
Early postoperative care in the post-cystectomy
patient is driven by the goals of minimizing complications, educating patients, and providing cost-effective care. The use of clinical pathways has been
shown to facilitate attainment of all of the above
goals. The pathways provide guidelines for patient
care, but the clinician should not hesitate to diverge
from the pathway based on clinical event. Routine
postoperative ICU monitoring is not necessary.
Chang et al. reported on 304 patients after radical
cystectomy, 94% of whom were admitted to the gen-
b) Urinary Catheters
Decompression of the detubularized bowel segment
used for the neobladder is critical to ensuring good
healing of the suture lines and prompt emptying of
250
last 3 aspects are covered in other sections. Cancer
recurrence remains a major concern for the patient
and the physician. Tumor can recur either locally or
distantly. Local recurrence may occur in the remaining urothelium which includes the urethra, the ureter,
and the renal pelvis, or may present as local recurrence in the pelvis. Distant recurrence may manifest
as lymphatic or remote organ spread. In order to
detect these recurrences at the earliest time, followup protocols were established based on history, physical examination, laboratory studies, and imaging.
the neobladder. The urinary catheter should be irrigated frequently to clear the bladder of mucus,
beginning on the first postoperative day [102]. It is
important that the patient be adept in catheter irrigation in order to avoid postoperative mucus retention
and possible compromise of the neobladder. The
duration of catheter drainage is individualized, but
typically is 2 to 3 weeks. Ankem et al.’s recent study
demonstrated that routine pouchograms before
catheter removal were not necessary [103].
c) Postoperative Visit
a) History and Physical Exam
The first postoperative visit is typically 2 to 3 weeks
after surgery, at which time the Foley catheter is
removed. After Foley removal, the patient is instructed to empty the neobladder regularly (every 2-4
hours). Patients are taught to intermittently selfcatheterize if necessary to accomplish this goal;
hypercontinence is more common in women than in
men. Patients should be told that the normal sensation of bladder fullness will be absent, although most
patients report an awareness of pelvic sensation that
they will recognize as filling of the neobladder [104].
Patients also need to be taught how to void with a
neobladder. Pelvic floor muscle exercises, as well as
increasing intraabdominal pressure (using the Valsalva or Crede maneuvers), allows controlled voiding
and continence between voids [105,106]. Adequate
fluid intake should be encouraged to facilitate voiding and minimize the likelihood of obstruction by
mucus [107].
Patients are evaluated postoperatively at regular
intervals. The majority of patients who recur do so
in the first 2 years after surgery. Thus, most authorities recommend close observation during the first 24
months [80,108]. Patients are usually evaluated and
examined at months 1, 3, 6, 12, 18, and 24 postoperatively, then annually thereafter for at least 5 years.
A careful interval history and physical examination
(including pelvic or rectal examinations) should be
performed as these elicit symptoms of tumor recurrence or metabolic derangement. Complaints such as
weight loss, progressive weakness, or extremity
numbness may raise suspicion for malnutrition or
vitamin B12 deficiency. Hematuria or persistent
pelvic, perineal, or bone pain may be manifestations
of local tumor recurrence or distant metastases.
b) Imaging
Postoperative imaging should focus on morphologic
changes in the upper tracts as well as detection of de
novo urothelial tumors and surveillance for possible
pelvic recurrence and distant metastatic disease.
Imaging is also useful for diagnosis and management
of postoperative complications [109]. The choice of
imaging modality is based on patient characteristics
as well as clinical indications. Computed tomography and ultrasonography are useful in searching for
extrinsic mass lesions such as urinoma, abscess,
hematoma, lymphocele, or recurrent tumor. Surveillance for upper tract recurrence may be performed by
intravenous urography, or, more recently, CT urography. Ultrasonography and magnetic resonance urography are useful in patients with renal insufficiency
or contrast allergy [110]. Bone scans are only indicated in patients with bone pain suspicious for
metastases or in patients with advanced disease (≥
T3 and pN+) [111].
Summary
Postoperative care of patients after neobladder
construction is focused on minimizing complications as well as providing patient education. Prophylactic measures should be employed to reduce
the occurrence of predictable complications.
Early involvement of the patient and family in
care of the neobladder is invaluable in establishing realistic expectations for recovery, improving
communication with members of the health care
team, and promoting well-being.
7. LONG-TERM FOLLOW-UP
Follow-up after radical cystectomy and neobladder
formation should address the following aspects:
local and distant cancer control, long-term renal
function, long-term metabolic abnormalities, and
long-term functional outcome of the neobladder. The
c) Urine Cytology and Urethral Wash
The choice of urinary diversion may alter the cyto-
251
ilar to that in individuals with a native lower urinary
tract. In fact, Henningsohn et al. found similar wellbeing and subjective quality of life (QoL) in recurrence-free Danish patients as in a frequency-matched
control population (Level 3, [120]). Is this result
merely an expression of the well-known “response
shift” or is orthotopic substitution a true restitutio ad
integrum in most aspects of life? A major obstacle
for all researchers in the field is the lack of a universal definition of the term “quality of life.” Thus, it
may differ between cultures, countries, and, consequently, study groups. It is doubtful if the introduction of “health-related quality of life” has enhanced
our ability to determine what to include or to leave
out, as it is unlikely that one can divide quality of life
into its health- and non-health related components.
The conceptual vagueness is impressively reflected by the whole host of measuring modalities (open
or structured face-to-face interview, telephone interview, proxy rating, and self-report), and the multitude of generic and disease-specific questionnaires
available. Ad hoc questionnaires have often been
used until recently. Especially in postal questionnaire
surveys, missing data and low response rates remain
major problems. The use of a neutral third party for
carrying out studies may be of importance (Level 2,
[121]). Today, it is agreed that instruments used
should be tested for validity and reliability. Wellknown generic instruments include SF-36, SIP, NHP,
and EQ. The instruments HADS, POMS, PAIS, and
BDI measure mental and psychological distress. The
most commonly used cancer-specific instruments are
QLQ-C30 from the EORTC, FLIC, FACT-G, and
CARES-SF. There are a few bladder cancer specific
instruments available (QLQ-BLM30 and QLQ-BLS
24 from EORTC, FACT-BL, and recently FACTVCI). A relevant question is when adaptation after
cystectomy is optimal. Kulaksizoglu et al. studied
patients prospectively and found that the time frame
for adaptation is about 1 year (Level 2, [122]). In the
study by Hardt, mental quality of life showed a slight
increase and physical quality of life a slight decrease
from preoperative assessment to follow-up at 1 year
(Level 2, [123]). Speculated reasons for the change in
mental quality of life were that fear and worry from
initial diagnosis and upcoming surgery disappears
after surgery or the influence of response shift (a
shift in patients judgment of quality of life). For
physical quality of life, diversion of urine and
abdominal scar were speculated explanations. Coping strategies were studied, and a buffering effect of
a continent diversion for depressive coping on mental quality of life was noted.
morphologic features of urothelial cells [112]. Our
literature search found no studies evaluating voided
cytology following neobladder diversion; however,
we believe that urine cytology does have a role in
surveillance, especially in high-volume centers with
experienced cytopathologists. More commonly, urethral wash cytology is used [111,113]. Cytology from
urethral washings is both sensitive (90%) and specific (100%) [113,114], and permits early diagnosis of
local urethral recurrence, hopefully improving survival [115-117]. However, a recent retrospective
analysis from Memorial Sloan Kettering Cancer
Center found no difference in survival between
patients with symptomatic urethral recurrences and
those who were diagnosed by urethral wash cytology
[118].
d) Laboratory Studies
At each patient visit, a complete blood count and
comprehensive metabolic panel should be performed. In patients with ileal neobladders, vitamin
B12 and folic acid levels are measured 2 years after
surgery. Urinalysis and urine culture are not routine
but may be helpful in symptomatic patients. It is
important to remember that urine cultures from
neobladders (unlike conduit diversions) are typically
sterile. However, about half of neobladder patients
who void normally will have a positive urine culture.
More than half of these patients will develop uncomplicated urinary tract infection and 18% will develop
urosepsis over a 5-year period [119].
Summary
Long-term follow-up of patients after neobladder
diversion is centered on surveillance for local and
distant metastatic disease, functional outcome of
the neobladder, preservation of renal upper tracts,
and early detection and treatment of metabolic
abnormalities. Using a scheduled follow-up protocol enables both the clinician and the patient to
easily identify the laboratories and imaging to be
performed at each interval.
8. QUALITY OF LIFE AFTER RADICAL
CYSTECTOMY
At present, the optimal form of urinary diversion
after cystectomy for muscle-invasive bladder cancer
remains a controversial issue. It has been suggested
that orthotopic bladder substitution allows a life sim-
252
a) Conduit Diversion versus Continent Cutaneous
Diversion
this was common in conduit patients. However, only
54% of the patients returned the questionnaire.
There is only 1 prospective study, first reported by
Hardt et al. (Level 2, [123]). They found that perceived global satisfaction was high with both methods and that the majority of patients would choose
the same method again. An extension was recently
published [124]. Mental quality of life showed a
slight increase and physical quality of life a slight
decrease from preoperative measurement to followup at 1 year after surgery. This report focused on coping strategies.
Henningsohn et al. studied sources of symptominduced distress and found sexual dysfunction to be
the most distressing after cystectomy in all 3 types of
reconstruction (Level 3, [143]).
Similar results, without differences between the
groups, were obtained in 5 retrospective studies,
which all used ad hoc instruments (Level 3, [125129]). These studies all note that stomal problems are
more frequent among conduit patients.
e) Conduit Diversion versus Anal Diversion
b) Conduit Diversion versus Orthotopic Bladder
Substitution
Summary
Since 1995, 8 studies, all retrospective, have been
published (Level 3, [130-137]). All except 3 used
established validated instruments [130-132]. One of
the studies included only 6 conduit patients. Apart
from that study, only the study by Hobisch shows
superiority for orthotopic bladder substitution [133].
QLQ-C30 was used and patients with neobladders
scored significantly better than patients with conduits in all functional domains (physical, role, emotional, cognitive, and social). While only 36% of
patients with conduits would recommend the operation to a friend, 97% of the patients with neobladders
would.
The published literature on quality of life after
radical cystectomy is rather extensive. However,
the scientific quality is rather low, and flaws in
patient selection and methodology are common.
There is no randomized controlled study. Such a
study is desirable, but probably difficult to conduct. Published evidence does not support an
advantage of one type of reconstruction over the
others with regard to quality of life. An important
reason is probably that patients are subjected to
method-to-patient matching preoperatively and
thus prepared for disadvantages and advantages
with the different methods.
The other studies failed to show a difference [134137]. Both Fujisawa et al. and Salinas et al., using
SF-36, found general health and emotional functioning below a US control population.
9. RENAL FUNCTION AFTER URINARY DIVER-
d) Continent Cutaneous Diversion versus Orthotopic Bladder Substitution
The literature contains 3 retrospective studies (Level
3, [144-146]). In none of them were there any differences with regard to mode of diversion.
There is only 1 study published. Satoh et al. found no
differences in overall quality of life, but rectal reservoir patients scored in some items (Level 3, [147]).
SION
An important requirement for reconstruction of the
lower urinary tract is that it should not jeopardize the
integrity of the upper urinary tract. Development of
partial or complete obstruction of the urine flow,
reflux of infected urine, and formation of stones are
all factors that may adversely affect the renal function. A very large number of techniques for
ureterointestinal anastomosis have been described,
and so far no single method has proved superior to
the others.
c) Conduit Diversion versus Continent Cutaneous
Diversion versus Orthotopic Bladder Substitution
This form of comparison was carried out in 6 studies,
2 of which are prospective and consecutive (Level 2,
[138,139]). Most patients reported practical or emotional problems with no differences between the
groups.
Similar results were obtained in the retrospective
studies by Hart et al. and by Kitamura et al., apart
from conduit patients reporting more problems with
bathing habits (Level 3, [140,141]). The study by
McGuire et al. found a difference in only 1 single
item in SF-36 (Level 3, [142]). Thus, patients with
continent reconstruction did not differ from the normal population in degree of mental distress, while
Most clinical reports published on renal function
after urinary diversion are retrospective. Comparison
between studies is therefore difficult due to differences in patient age, underlying disorder, the use of
radiotherapy, preoperative and postoperative routines, and the duration of the follow-up. Type of
253
ileal urethral Kock pouch with an afferent nipple
valve (Level 2, [151]). The incidences of ureteric
stricture and reflux were similar.
suture material and the use and duration of stenting
are other factors that might be of importance. The
functional status of the upper urinary tract prior to
the urinary diversion is most valuable information
but is often lacking in clinical reports. Another problem relates to the methods of measuring renal function after urinary diversion. Many reports rely on
serum creatinine and urography, but both are imprecise for the purpose. More accurate methods of estimating renal function take into account the excretion
and the plasma level of a substance freely filtered
trough the glomeruli, such as 51Cr-EDTA and iohexol.
b) Conduit Diversion - Case Series
In a large series by Madersbacher et al., patients had
been followed for a minimum of 5 years after ileal
conduit diversion (Level 3, [152]). Ten percent of the
patients developed stenosis of the ureterointestinal
anastomosis, 20% developed upper tract stones,
increasing to 38% after 10 years. Morphological and
functional deterioration developed in 27%, most
often in the form of hydronephrosis or shrunken kidney. Renal pathology was present in 40% after 5
years, increasing to 80% after 10 years. Iborra et al.
reported impaired renal function in 14% of patients
followed for more than 10 years (Level 3, [153]). A
similar figure was noted by Fontaine et al., who
found a nonsignificant decrease in creatinine clearance in 22 patients followed for more than 5 years
after jejunal conduit diversion (Level 3, [154]). Of
these, 2 had a decrease in creatinine clearance of
more than 20% due to ureterojejunal obstruction.
Refluxing anastomoses are most often direct end-toside, commonly used for ileal conduit diversion. The
most commonly used techniques for implantation
into an ileal segment are antirefluxing anastomoses the afferent loop as in the Studer pouch, the intussuscepted ileal nipple valve as in the Kock pouch,
the Le Duc technique, the split-cuff ureteric nipple,
and the serous-lined extramural tunnel, and, for
implantation into a colonic segment, the submucous
tunnel.
c) Continent Reconstruction – Case Series With
Information on GFR
a) Randomized Studies
The literature contains only 3 randomized studies, all
of moderate methodological quality. Kristjansson et
al. compared conduit diversion to continent cutaneous diversion, antirefluxing ureterointestinal anastomosis to refluxing anastomosis for conduit diversion, and ileal conduit versus colonic conduit (Level
2, [148,149]). No statistically significant differences
were found with regard to symptomatic urinary tract
infection, number of ureterointestinal anastomotic
strictures, and incidence of GFR deterioration. With
a mean follow-up of 10 years, the mean GFR fell
from 88 to 71 mL/min in patients with ileal conduits
and from 88 mL/min to 65 mL/min in patients with
colonic conduits. Corresponding figures for patients
with continent diversions were 100 mL/min and 85
mL/min, respectively. Scarring was more common in
refluxing than in antirefluxing units (P = 0.06).
Apart from the study by Kristjansson, there are 2
studies which provide information on GFR. In
patients with orthotopic Kock ileal neobladders,
Steven et al. reported a median clearance of 98
mL/min preoperatively, which decreased to 93
mL/min at 3 years and 90 mL/min at 5 years (Level
3, [44]). Ureteral obstruction occurred in 3%, 2.4%
being due to afferent nipple stenosis and only 0.6%
due to stricture of the ureterointestinal anastomosis.
Reflux was noted in 9% to 13% and was not associated with loss in GFR. Jonsson et al. studied patients
who had undergone continent cutaneous diversion
using a Kock reservoir and found a significant reduction in GFR in patients with long-term follow-up
(Level 3, [155]). However, this decrease was of the
same magnitude as would be expected in a control
population with increasing age. Reoperations due to
afferent nipple dysfunction or stricture of the
ureteroileal anastomosis were necessary in 15% of
the patients.
Studer et al. compared antirefluxing anastomoses
(ileal nipple valve or split-cuff ureteric nipple) in a
short afferent segment with refluxing ureterointestinal anastomosis to an 18 to 20 cm afferent segment
in patients with ileal neobladders and found the former to be associated with a statistically significant
higher incidence of upper tract dilatation, but this
was based on a low number of patients and a wide
confidence interval (Level 2, [150]).
d) Continent Reconstruction – Other Case Series of
Well-known Techniques
Thoeny et al. evaluated the upper urinary tracts in
patients with Studer neobladders followed for 5
years or more (Level 3, [156]). De novo shrinkage of
the parenchyma was observed in only 1% of preoperatively normal renal units. Stricture of ureteroin-
Osman et al. compared the ileal W neobladder with
the serous-lined extramural tunnel technique to the
254
Summary
testinal anastomosis occurred in 3% of 148 units. In
9%, dilated upper tracts were noted, but without
obstruction, confirming that dilation does not always
result from obstruction. Mean serum creatinine was
98 µmol/L preoperatively, 103 µmol/L at 5 years,
and 83 µmol/L at 10 years postoperatively. Hautmann et al. reported on 363 patients with ileal W
neobladders (Level 3, [1]). Ureteric implantation was
by the Le Duc technique or a chimney. Reoperation
for ureterointestinal stricture was done in 9% of the
patients, and renal deterioration occurred in 1%.
With the latter technique, a stricture rate of 1% was
recently reported [19]. Elmajian et al. reported on the
Kock ileal neobladder and found afferent nipple
stenosis, reflux, and ureterointestinal anastomotic
stricture in 2.4%, 2.0%, and 1.4% of the patients,
respectively, after median follow-up of 3.6 years
(Level 3, [157]). In the study by Abol-Enein et al. on
the W-shaped ileal neobladder with serous-lined
extramural ureteral implantation, anastomotic stricture occurred in 4% of implanted ureters and reflux
was noted in 3% (Level 3, [83]). In the 2 latter
reports, information on renal function is not given. In
patients with right colon bladder substitutions or
continent cutaneous diversions, Månsson et al.
reported a stricture rate of 2% in patients with Le
Duc ureteric implantation (Level 3, [81]). The serum
creatinine levels of 11 of 162 patients rose over 120
µmol/L, and 3 of these rose to over 165 µmol/L after
mean follow-up of 5 years. Using an ileocecal pouch
for bladder substitution (Mainz pouch), stricture of
the ureterointestinal anastomosis (submucous tunnel) was reported in 7% of renal units, but data on
renal function was not given (Level 3, [158]). In a
study of patients with Mainz pouch I followed for 5
to 16 years, median serum creatinine was 1.0 mg/dL
(88.4 µmol/L) with 25th and 75th percentiles of 0.9
and 1.2 mg/dL (79.6 and 106.1 µmol/L) (Level 3,
[58]). Recent publications suggest that an antirefluxing anastomosis is unnecessary in patients with low
pressure pouches, giving low figure rates for strictures after short follow-up [19,159-161].
While there is a rich literature on urinary diversion, few publications give data on renal function.
The majority of reports are case series with a low
level of evidence. The literature does not support
benefits of one type of ureteric implantation over
another. Prospective randomized studies are needed to clarify this issue. Renal function decreases at
long-term follow-up, but this is at least partly due
to normal aging. There is no evidence to suggest
that patients with continent reconstruction do less
well than conduit patients with regard to renal
function.
10. URINARY TRACT INFECTION
Normal urothelium has several defense mechanisms
against bacteria. Voiding function is a physical action
to wash out bacteria, which is most primitive but
effective. Urothelium has inhibitory action against
bacterial adherence. One of the reasons why bacteriuria frequently occurs when bowel is used as urinary
diversion is that bowel epithelium lacks an inhibitory action against bacterial adherence. Acidic or high
osmolar urine itself also has some anti-bacterial
actions. Specific and non-specific immune system
components such as polymorphonuclear leukocytes
(PMN) or secreting immunoglobulins also play
roles. In patients with urinary diversions, some of
these mechanisms are impaired and susceptible to
bacterial infection. There are several types of urinary
diversions and the characteristics of urinary tract
infections vary according to each type of urinary
diversion. Since there is a big difference between
intubated and tubeless urinary diversions, these will
be discussed separately.
a) Intubated Cutaneous Ureterostomy
Although catheterless urinary diversion should be
considered permanent, intubated cutaneous ureterostomy or percutaneous nephrostomy is applied to
selected patients with high-risk conditions. In these
patients, UTI is inevitable and bacteria in these
patients are very similar to those detected in usual
complicated UTIs. Frequently identified bacteria are
Proteus species, Escherichia coli, Enterococcus
species, and Klebsiella species. Although bacteriuria
is inevitable in these patients, pyelonephritis occurs
especially when urine passage is impaired. Thus, the
only way to prevent serious UTI in these patients is
to change the catheter periodically with appropriate
administration of antibiotics when needed.
e) Continent Anal Diversion
In a medium-term follow-up study, Bissada et al.
reported stable renal function in 92% of patients after
classic ureterosigmoidostomy (Level 3, [162]).
Radiographic deterioration was present in 23% of the
renal units, and was severe in 7%. Bastian et al. also
found stable renal function after Mainz pouch II
diversion (Level 3, [163]). Pyelonephritis occurred in
14% of the patients.
255
b) Tubeless Cutaneous Ureterostomy
conduit indicated that urinary infection was most
prevalent in conduits having irregular, weak, peristaltic contractions.
It has been thought that tubeless cutaneous ureterostomy is feasible only when the ureter is dilated [164].
In fact, ureteral ischemia with stricture formation
and stomal stenosis are the most common complications of ureterostomy. The rate of stenosis varies
from 15% to 67%, according to various reports. In
these patients, subsequent pyelonephritis due to
urine obstruction is a crucial problem. Matsuda et al.
reported that 22 (56%) of 39 patients with tubeless
cutaneous ureterostomies showed bacteria in urine
collected from the renal pelvis with a double lumen
catheter [165]. However, pyuria was observed only
in 6 (15%) patients. Thus, most of the bacteria is
clinically insignificant in these patients. Urine passage seems to be the most important factor for UTI
in patients with tubeless cutaneous ureterostomies insignificant bacteriuria will become significant
when urine passage is impaired.
Summary
In summary, we have to pay much attention to
UTI in patients with ileal conduits. This complication is observed early and late. Urodynamic
evaluation is recommended in patients with ileal
conduits who have recurrent UTIs.
d) Cutaneous Continent Diversion
Patients with continent diversions also have a significant incidence of bacteriuria. Indeed, the rate of positive urine culture was reported to be 67% with ileal
reservoirs [169], 67% with cecal reservoirs [170],
71% with Kock pouches, and 56% with Indiana
pouches [171]. Bacterial species in urine are E. coli,
Pseudomonas species, Klebsiella species, Proteus
species, and Enterococcus species, which are very
similar to usual complicated UTI. The microbial
flora of stoma and peristomal skin are different from
that of a continent urinary reservoir [170]. The reasons for the increased incidence of bacteriuria are
unclear, but it is likely that the intestine is incapable
of inhibiting bacterial proliferation in contrast to the
urothelium. Comparing to cutaneous ureterostomy or
ileal conduit, clinically significant UTI is less common and asymptomatic bacteriuria in patients with
continent ileal reservoir should not be treated with
antibiotics [169]. An antireflux technique of
ureterointestinal anastomosis, such as the Le Duc
technique, contributes to a low incidence of UTI
[172].
c) Ileal Conduit
As previously mentioned, an increased incidence of
bacteriuria, bacteremia, and septic episodes occurs in
patient with bowel interruption. Bruce et al. intensively studied UTI in patients with ileal conduits
[166]. According to his report, the incidence of bacteriuria was 84%, and 14% had clinical evidence of
pyelonephritis. This incidence of bacteriuria is similar to other reports [167]. Proteus species, Klebsiella
species, E. coli, Pseudomonas species, Enterococcus
species, and yeast are frequently-detected pathogens.
Electron microscopy examination of cup biopsy
specimens from the conduit shows virtually no bacteria adhering to the columnar cells of the conduit,
although Gram positive cocci were seen adhering to
the keratinized cells from the mucocutaneous junction [166]. They also found that a number of the bacterial isolates from the conduits were found to attach
to human urothelial cells in vitro, indicating these
pathogens can cause retrograde infection. Recently,
Madersbacher et al. reported on long-term outcomes
after ileal conduit diversion [152]. They demonstrated a high rate of conduit-related complications
including urolithiasis; infection; and metabolic, conduit, bowel, stoma, and renal dysfunction. Clinically
evident UTI was observed in 30 (23%) of 131
patients with ileal conduits who were followed for
more than 5 years. Urosepsis occurred in 5 patients
(3.8%). Minton et al. studied the relationship
between UTI and urodynamics of conduits [168].
They showed that the longer a patient survives following diversion, the greater the chances for subsequent urinary infection. Manometric studies of the
e) Orthotopic Neobladder
There are few studies concerning UTI in patients
with orthotopic neobladders [119,173]. Wullt et al.
reported that 67% of the specimens from patients
with neobladders were culture-positive, and half of
them contained uropathogenic species, such as E.
coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterococcus faecalis, which are similar to
those found in other types of urinary diversion [173].
Bacterial colonization was strongly correlated with
residual urine. However, all the patients in this study
were asymptomatic. Thus, the necessity of antibiotic
treatment and clinical significance of bacteriuria in
these patients are controversial. Wood et al. reported
that 67% of the patients with orthotopic neobladder
256
Both incorporation of an afferent or efferent limb for
ureteral anastomosis and orthotopic anastomosis of
the ureters directly into the reservoir, with or without
an antireflux technique, are feasible [2,179,181,182].
had a positive urinalysis, and 51% of these patients
had a positive urine culture [119]. The overall rate of
UTI was 39%, and 12% had urosepsis. In fact, more
studies seem to be needed to make conclusions concerning UTI in patients with orthotopic neobladders.
In an animal experiment of a rat bladder augmentation model using ileum, Nakano et al. reported that
the type I pilus of E. coli is one of the main causes of
asymptomatic bacteriuria after urinary reconstruction using ileum [174].
1. PATIENT SELECTION
a) Patient Factors: For
The primary patient factor is the “patient’s desire for
a neobladder.” The patient needs a certain motivation
to tolerate the initial and sometimes lasting inconveniences of nocturnal incontinence associated with a
neobladder. Most patients readily accept some
degree of nocturnal incontinence for the benefit of
avoiding an external stoma and pouch, but not all
patients do, and realistic expectations of the functional outcome are essential for both the surgeon and
the patient [9].
Summary
Bacteriuria is inevitable in intubated cutaneous
ureterostomy and significant UTI occurs frequently. Although bacteriuria is also observed in more
than half of patients with tubeless cutaneous
ureterostomy, clinical UTI occurs less provided
urine passage is not obstructed. About two-thirds
of patients with urinary diversions using intestinal
segments show bacteriuria. UTI is a rather crucial
problem for patients with ileal conduits even after
long follow-up. In patients with continent urinary
reservoirs and orthotopic neobladders, UTI is not
a serious complication, as long as urine is voided
smoothly.
The psychologically-damaging stigma to the patient
who enters surgery expecting a neobladder but
awakens with a stoma plays an increasing role. It
should always be remembered that in many parts of
the world, a bag may either be socially unacceptable
or economically unrealistic as a long-term solution.
These pressures drive the urologist toward some
form of continent urinary diversion, and, although
rectal pouches have been used widely as alternatives
to conduits, continent catheterizable reservoirs or
orthotopic bladder substitutes in particular represent
attractive options [19].
b) Patient Factors: Against
II. ORTHOTOPIC
RECONSTRUCTIONI
There are still patients who are better served with a
conduit. Patient factors against a neobladder are:
1. If the patient’s main motivation is to “get out of
the hospital as soon as possible” and resume normal, rather sedentary activities. Many frail
patients undergoing cystectomy will have less disruption of normal activities with a well-functioning conduit than an orthotopic reservoir associated with less than ideal continence.
Ileal reservoirs are the most common form of
neobladders used worldwide. There are 3 major categories:
1. The Hemi Kock, originally developed by Kock
and popularized by Skinner and associates
[175,176]. The most recent modification is technically complex, time consuming, and has yet to be
widely adopted [2].
2. The “little old lady” living in social isolation.
3. No concern about body image. Most older patients
do not have the same cosmetic concerns that a
younger patient might have, and their main goal is
returning to their previous lifestyle, which is often
quite sedentary [183].
2. The second type of ileal reservoir initially
described by Studer, which has the advantage of
an afferent limb that facilitates ureteroileal anastomosis without valve formation [177].
3. The third type of ileal reservoir is the ileal
neobladder, a W-shaped reservoir as described by
Hautmann and coworkers [178-180]. Its obvious
advantages are the best early continence rates as a
consequence of having the greatest volume of all
reservoirs.
c) Patient Selection Criteria: Oncologic Factors
Following cystectomy, the rhabdosphincter must
remain intact. Nevertheless, the cancer operation
must not be compromised. This concern applies to 2
aspects of selection: urethral tumor recurrence in
257
men and the use of orthotopic replacement in
women.
desire to offer orthotopic diversion whenever possible, some patients do not qualify on the basis of current clinical judgment. An ileal conduit remains an
expedient, safe, and appropriate method of diversion
in these patients. Many factors go into the decision to
perform a urinary diversion and must be kept
paramount in discussing the pros and cons of each
method with the patient and his or her family.
1. One of the initial deterrents to orthotopic diversion
is the risk for urethral recurrence of cancer. See
below.
2. Orthotopic bladder substitution for women with
invasive bladder cancer has been popularized
recently [184-186]. For oncologic justification see
below.
2. IS REFLUX PREVENTION NECESSARY?
Increasing experience with orthotopic reconstruction
has fostered less restrictions for patient selection
based on tumor stage. Should extensive pelvic disease, a palpable mass, or positive but resectable
lymph nodes preclude a neobladder because of the
high propensity for a pelvic recurrence or distant
relapse? There is no convincing evidence that a
patient with an orthotopic diversion tolerates adjuvant chemotherapy less well or that a pelvic recurrence is any more difficult to manage with a
neobladder than after an ileal conduit. Patients can
anticipate normal neobladder function until the time
of death [187].
High pressure reflux with or without infection may
lead to renal damage (Level 3, [188]). Antireflux
procedures were therefore developed in order to
reduce this risk following urinary diversion. Some of
these techniques were developed prior to the introduction of orthotopic reconstruction, and their continued use with orthotopic reconstruction has been
rather random and unscientific. Many surgeons with
expertise in the field of reconstruction have abandoned any form of antireflux procedure with orthotopic reconstruction (Level 4, [19]). The need for
reflux prevention with a low pressure detubularized
orthotopic reconstruction is not the same as with a
conduit, continent cutaneous diversion, or
ureterosigmoidostomy. There are many potential
causes for deterioration in renal function after urinary tract reconstruction. Randomized controlled
trial evidence is therefore important in order to draw
valid conclusions about the need for antireflux procedures. Unfortunately, few studies have been carried out in humans. The main problem with antireflux procedures is increased surgical complexity,
which results in a higher complication rate. In fact,
the particular problem of renal deterioration that one
is trying to avoid may be seen more frequently as a
result of obstruction at the ureteroileal junction.
However, adjuvant chemotherapy may substantially
weaken the patient and prolong the time for neobladder maturation. Nevertheless, our philosophy
respects the patient’s desire for a neobladder; if the
patient is strongly motivated, he or she gets a
neobladder. Even though the patient has a poor prognosis and relapse is likely to occur, we still try to
construct the diversion they want. Previous radiation
therapy, especially with an advanced cancer, usually
mitigates against an orthotopic diversion but does
not absolutely preclude it. However, all patients
should be informed that diversion to the skin either
by a continent reservoir or ileal conduit may be necessary due to unexpected tumor extent, and an appropriate stoma site should be marked on the abdominal
wall beforehand.
Studer and colleagues prospectively randomized 70
patients undergoing orthotopic reconstruction to
have either a freely refluxing end-to-side ureteroileal
anastomosis into an afferent isoperistaltic ileal limb
or an antirefluxing nipple valve (Level 2, [150]).
Ureteroileal stenosis resulting in severe upper tract
dilation was seen in 13.5% of those ureterorenal
units with antirefluxing nipple valves compared with
only 3% of those with an afferent tubular segment.
Although follow-up in this study was only mediumterm, most patients were followed until death and the
trial was abandoned as there were significantly more
complications with intussuscepted nipple valves.
Perhaps this form of antireflux mechanism has a particularly high complication rate, but others groups
have reported high rates of stenosis using other
d) Current Practice
Despite the fact that orthotopic bladder replacement
provides the ideal method of urinary diversion after
cystectomy, many patients treated outside of centers
that are dedicated to neobladder reconstruction
receive an ileal conduit. Why? These patients often
have adverse clinical factors such as increased age,
more comorbidities, and more previous cancer therapy, including patients with previously deemed unresectable cancers undergoing desperation cystectomy
or after failed combined radiation therapy and
chemotherapy regimens [183]. Thus, despite a strong
258
that a difference would be seen with an orthotopic
bladder substitute in which urine is usually sterile.
One should also remember that antireflux valves will
not spare the upper tract from the effects of sustained
high pressure in a bladder substitute. High pressure
will close the valve, and, as urine production continues, pressure in the upper tract will increase until the
bladder pressure reduces (Level 2, [150]).
forms of antireflux techniques as discussed below.
Subsequent longer-term follow-up of 76 patients at a
mean of 84 months after afferent ileal limb bladder
substitution showed only 1% of ureterorenal units to
have lost cortical thickness on ultrasound, which was
associated with ureteroileal stenosis (Level 3, [156]).
An afferent ileal limb does not prevent reflux altogether, but under normal voiding conditions, without
an overfilled reservoir, reflux is minimal as the afferent tubular segment acts as a dynamic antireflux system. Videourodynamics do not show reflux of contrast medium during the Valsalva maneuver as pressure rises simultaneously in the bladder substitute
and the upper tract (Level 2, [150]). Although measurement of renal cortical thickness and serum creatinine will not detect more minor degrees of renal
deterioration that would be picked up with radioisotope measurement or glomerular filtration rate, it
seems that the afferent ileal limb is safe in terms of
renal function at 7 to 15 years.
Summary
In conclusion, we believe that a simple end-toside freely refluxing anastomosis into an afferent
limb of a low pressure orthotopic reconstruction,
in combination with regular voiding and close follow-up, is the procedure with the lowest overall
complication rate. Continued peristalsis in the
afferent ileal limb reduces but does not eliminate
reflux. The potential benefits of “conventional”
antireflux procedures in combination with orthotopic reconstruction seem outweighed by the
higher complication and associated reoperation
rates.
As a result, others have now developed variations on
this theme such as the 3 to 5 cm chimney reported by
Hautmann and Simon, who found a reduction in the
ureteroileal stenosis rate of 9.5% in 363 consecutive
patients with the Le Duc antireflux procedure to 1%
in 195 subsequent patients with freely-refluxing
anastomosis (Level 3, [187]).
3. UPPER TRACT SAFETY (LONG-TERM)
Long-term safety of the upper tracts is an essential
requirement for successful lower urinary tract reconstruction. There are many potential reasons for deterioration in renal function including transmission of
high bladder pressure to the upper urinary tract
(reflux or functional obstruction), stone formation,
infection, and physical obstruction at any site
(ureteroileal being the most common). The pathological changes seen with varying etiologies are the
same, and, thus, the cause at the time of detection
may not be obvious. In addition to a natural agerelated decline, there may be many nonurologic
causes for declining renal function such as hypertension, diabetes, drugs, and so on. A number of retrospective studies have reported renal functional and
morphological deterioration ranging from 13% to
41% after ileal conduit diversion (Levels 2 and 3,
[152,189,190]). Following continent cutaneous
diversion, Kristjansson and colleagues reported a
decrease in renal function in 28% of patients 11 years
after cecal reservoir creation (Level 2, [148]). Akerlund and colleagues reported upper tract dilation at a
mean of 6.6 years after Kock pouch formation (continent ileal reservoir) in 5 of 17 patients (29%),
which was associated with scarring in 2 (Level 2,
[191]). Only 1 patient (6%), however, had an abnormal creatinine at the last follow-up, though 4 had a
In a nonrandomized study of refluxing and nonrefluxing ureteroileal anastomoses in both Indiana
pouch and ileal orthotopic bladder substitutes, Pantuck and colleagues also found a statistically significantly higher rate of benign ureteroileal stenosis with
nonrefluxing anastomoses (13%) compared to a simple end-to-side anastomosis (1.7%) at a mean follow-up of 41 months (Level 3, [159]). They found no
difference in the rates of hydronephrosis, pyelonephritis, upper tract stone formation, or serum creatinine between those with refluxing or nonrefluxing
anastomoses. In contrast, Kristjansson and colleagues, in a randomized study of refluxing versus
nonrefluxing ureteroenteric anastomoses with either
an ileal or colonic conduit, found the ureteroileal
stricture rate to be unrelated to the mode of implantation (Level 2, [148]). The overall stricture rate was
however higher than one might expect at 13.2% at a
mean follow-up of 10 years. (Since this report they
have modified antireflux techniques to a simpler submucosal tunnel.) They found no difference in reduction of GFR between kidneys with and without
reflux protection. If in a chronically infected conduit
system no difference in GFR is detected with refluxing and nonrefluxing techniques, then it is unlikely
259
4. CONTINENCE
low age-adjusted glomerular filtration rate (GFR) (3
of these had a low GFR preoperatively).
Continence following orthotopic urinary diversion is
dependent on an intact urethral sphincter mechanism
and pelvic floor, which are able to maintain a resistance pressure across the urethral continence zone
that exceeds the pressure generated within the diversion [19,192,193]. This latter pressure is influenced
by the size and configuration of the intestinal segment utilized for the diversion in accordance with the
law of La Place, pressure = tension/volume. Additional factors influencing continence include urethral
length and sensitivity, patient age and mental status,
intact pelvic nerve supply to the rhabdosphincter,
completeness of voiding, and presence or absence of
bacteriuria. The innervation to the pelvic rhabdosphincter includes the pudendal nerve and
intrapelvic somatic afferent sensory and efferent
motor fibers supplying the intrinsic urethral sphincter (Level 2 and 3, [194,195]). Multiple choices of
intestinal segment (ileal, ileocecal, folded right colon
or with ileal patch, or sigmoid) reconfigured in many
ways (see below) can each achieve large capacity
(more than 300 mL) and overall high levels of continence provided the principles of detubularization
and creation of a low pressure chamber are adhered
to as described earlier in this chapter. Continence
improves over time during the initial 6 to 12 months
postoperatively as the compliance of the diversion
increases, allowing storage of greater volume at
lower pressure [19,80]. Patients learn to void by performing a Valsalva maneuver in coordination with
relaxation of the pelvic floor, resulting in spontaneous voiding to empty the diversion. Objective
quantification of continence in various series utilizing specific techniques of orthotopic reconstruction
is hampered by a wide range of reporting methodology, including subjective and objective, arbitrary
definitions of degree of continence determined at
various time points postoperatively. Thuroff et al.
and Hautmann et al. provide a framework for reporting continence in urinary diversions that conforms to
the recommendations of the International Continence Society as reflected in Appendix 1, adapted
from Hautmann et al. [1,196]. Continence results
must be separated into day and night control and
evaluated among men and women separately.
There are few long-term reports of renal function following orthotopic reconstruction. In addition, reported methods of measuring renal function usually rely
on serum creatinine or radiological studies, both of
which have limitations. Serum creatinine only begins
to rise after a significant reduction in glomerular filtration, and the presence of upper tract dilation does
not necessarily equate to a reduction in renal function. Many studies are also retrospective with incomplete preoperative data. Measurement of preoperative and postoperative renal function using radioisotope studies would provide the best information on
the safety of orthotopic reconstruction with regard to
the upper tracts.
Thoeny and colleagues reported a prospective analysis of renal morphology and function in 76 patients
with a median follow-up of 84 months (range 60-155
months) after a low pressure ileal afferent limb bladder substitute (Level 2, [156]). Serum creatinine and
IVU were performed preoperatively and at regular
intervals postoperatively. Of 148 ureterorenal units,
141 (95%) showed no significant change in size or
parenchymal thickness. In 6 (4%), renal size and
parenchymal thickness decreased, and in 1 parenchymal thickness alone reduced. However, the majority
(5) of these ureterorenal units had preoperative renal
pathology such as dilation, obstruction, or scarring.
Loss of parenchyma from kidneys that were normal
preoperatively was seen in only 2 ureterorenal units
(1%) and was associated with ureteroileal stenosis.
Preoperative mean serum creatinine ± SD was 98 ±
19 µmol/L and at 10 years thereafter was 83 ± 27
µmol/L. Twelve of 76 patients (16%) had increased
serum creatinine, 5 of whom had preoperative dilation or obstruction. In this prospective study, renal
deterioration was seen only in the presence of preexisting renal pathology or postoperative obstruction. Nevertheless, more precise assessment of GFR
is missing.
Summary
In conclusion, renal deterioration following an
orthotopic reconstruction with an afferent ileal
limb is minimal at 10-year follow-up. Close follow-up is required in order to identify correctable
causes early, particularly ureteroileal stenosis.
Those with pre-existing renal pathology prior to
surgery seem to be at greatest risk of postoperative renal deterioration.
a) Day Continence
Daytime continence is achieved earlier postoperatively than nighttime continence [4]. The overall rate
of daytime continence that is “good or excellent” as
variously defined as either totally dry or with use of
1 pad per day 1 year following orthotopic diversion
260
is approximately 85% to 90% as shown in Table 5
(Level 3, [1,44,54,55,83,157,176,193,195,197-209]).
Nesrallah et al. found that elongated ileal neobladders had lower daytime continence than more spherical neobladders at 36 months postoperatively (41%
vs. 69%) but that the results were the same by 1 year
(89% vs. 87%) (Level 3, [208]). However, they noted
that by 1 year the spherical neobladders tended to
enlarge to greater capacity (820 mL vs. 460 mL), to
have a higher prevalence of postvoid residual urine
volume over 100 mL (52% vs. 14%, P < 0.05), and a
greater need for clean intermittent catheterization
(CIC) (19% vs. 0%, respectively). Hautmann reported that decreased functional urethral length after
surgery is associated with frequent or continuous
leakage when the patient is walking, more so than
during transient increases in stress-related rises in
abdominal pressure during activities such as sneezing or coughing [19]. Hugonnet et al. reported that
decreased urethral sensitivity at but not distal to the
membranous urethra in men with neobladders was
associated with higher rates of incontinence
[210,211]. Daytime continence rates may decrease 4
to 5 years postoperatively due in part to decreased
tone of the urethral sphincter with advanced age
[212]. Thus, patient age at the time of cystectomy
and urinary diversion is a relative factor in the decision for or against orthotopic reconstruction. Persistent severe incontinence following orthotopic urinary diversion may be treated by periurethral collagen injection or definitive placement of a urethral
sling or artificial urinary sphincter. The benefits of
collagen injections in this patient group have been
modest in degree and duration [213].
found similar rates of enuresis varying from 27% to
50% at increasing follow-up intervals beyond 12
months in male patients with either hemi-Kock or
Hautmann ileal neobladders (Level 3, [200,203]).
Patients with enuresis had higher pressures, maximal
volumes, postvoid residual urine volumes, and rates
of positive urine cultures, and lower maximal urethral pressures, flow rates, and compliance compared
to those without enuresis by univariate analysis as
shown in Table 7. However, in multivariate analysis
only the amplitude of uninhibited contractions and
increased postvoid residual volume remained associated with enuresis. Also, th